Endoscopic smart probe and method

ABSTRACT

An improved endoscopic device which is introduced into the intestinal tract of a living organism and which operates autonomously therein, adapted to obtain and store or transmit one or more types of data such as visual image data, laser autofluorescence data, or ultrasonic waveform data. In another aspect of the invention, an improved endoscopic device useful for implanting the aforementioned endoscopic smart probe is disclosed. In another aspect of the invention, apparatus for delivering agents including nanostructures, radionuclides, medication, and ligands is disclosed. In another aspect of the invention, apparatus for obtaining a biopsy of intestinal tissue is disclosed. In another aspect of the invention, apparatus for detecting the presence of one or more molecular species within the intestine is disclosed. Methods for inspecting and/or treating the interior regions of the intestinal tract using the aforementioned apparatus are also disclosed.

This application is a continuation-in-part of prior application Ser. No.09/817,842 entitled “Endoscopic Smart Probe and Method” filed Mar. 26,2001, which is a continuation-in-part of Ser. No. 09/259,194 filed Mar.1, 1999 now abandoned, both of which are incorporated by referenceherein in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the field of medical instrumentation,specifically to the use of smart technology within miniature remotedevices for the inspection, diagnosis, and treatment of internal organsof living organisms.

2. Description of Related Technology

Endoscopic and colonoscopic techniques are commonly used to inspect theaccessible upper and lower portions, respectively, of the humangastrointestinal tract. A traditional endoscopic inspection of a humanbeing (an example of which is the “EGD”) requires the patient to bepartially or completely sedated while a long, thin, tubular probe isintroduced into the esophagus, routed through the stomach, andultimately into the upper portion of the small intestine (duodenum).This tubular probe typically contains a self-illuminating fiber opticcable and viewing device to allow visual inspection of tissue in thevicinity of the probe tip. See, for example, U.S. Pat. No. 3,901,220,“Endoscopes” issued Aug. 26, 1975. However, due to the tortuous path,fragility, small diameter, and length of the digestive tract, prior artendoscopic inspection such as the aforementioned EGD is limited to onlythe stomach and upper portions of the small intestine. See FIG. 1.

Similarly, traditional colonoscopic examination utilizes a thin, tubularfiber optic probe inserted into the large intestine (colon) via therectum. Even the most penetrating colonoscopic inspections are limitedto the colon and the terminal portion of the small intestine (ileum),due again primarily to the tortuosity and fragility of the largeintestine and ileum. While a substantial number of diseases andconditions afflict the stomach, duodenum, colon, and ileum, severalothers may occur within the remaining, inaccessible portions of thegastrointestinal tract including the jejunum of the small intestine.

Both endoscopic and colonoscopic inspections further run a small butsignificant risk of physical damage to the patient, such as perforationof the duodenum or ileum, especially where disease has progressed to anadvanced stage and the surrounding tissue has weakened or degenerated.

Alternatively, non-invasive diagnostic techniques such as X-rayinspection (e.g., so-called “upper-GI” and “lower-GI” series), whichinvolves introducing barium or other contrast agents into the patient,are useful in identifying gross abnormalities, but require carefulinterpretation and are susceptible to misdiagnosis, shielding effects,and a plethora of other potential pitfalls. Furthermore, such techniquesexpose the patient to significant doses of ionizing X-ray radiationwhich ultimately may be deleterious to the patient's health.

The somewhat related technique of X-ray computed axial tomography (CAT)scanning provides information about the general condition of anindividual's intestinal tract and internal organs, yet does not possessthe necessary resolution to facilitate diagnosis of many types ofconditions. It also suffers from the drawback of exposing the patient tosubstantial quantities of X-ray radiation. CAT scans of the GI tractalso may require the use of ingested and/or intravenous contrast agents,the latter notably having a small but non-zero incidence of patientmortality. Furthermore, certain patients may not be given such contrastagents due to allergies or other pre-existing medical conditions,thereby substantially reducing the efficacy of the CAT scan as adiagnostic technique for these patients.

Magnetic resonance imaging (MRI) techniques, well known in the medicaldiagnostic arts, have certain benefits as compared to the aforementionedCAT scan, yet also suffer from limitations relating to resolution andinterpretation of the resulting images, and in certain instances therequired use of “contrast” agents. More recently, enhanced MRItechniques are being used to aid in the diagnosis and treatment ofCrohn's disease, yet even these enhanced techniques suffer fromlimitations relating to resolution, especially when the disease has notprogressed to more advanced stages.

Another related and well-known medical diagnostic technology is that ofautofluorescence endoscopy. Simply stated, autofluorescence endoscopyuses a light source having specific characteristics (typically acoherent source such as a laser) to illuminate a portion of tissue underexamination; the incident light excites electrons within the atoms ofthe tissue which ultimately produce a quantum transition thereinresulting in an emission of electromagnetic radiation (fluorescence)from the tissue at one or more wavelengths. Additionally, so-called“remitted” energy, which is incident or excitation energy reflected orscattered from the tissue under analysis, is also produced. Thefundamental principle behind the autofluorescence technique is thatdiseased or cancerous tissue has a different autofluorescence (andremitted light) spectrum than that associated with healthy tissue ofsimilar composition; see FIG. 2. Generally speaking, diseased tissueautofluoresces to a lesser degree at a given wavelength under the sameincident excitation radiation than healthy tissue. See, for example,U.S. Pat. No. 4,981,138, “Endoscopic Fiberoptic FluorescenceSpectrometer” issued Jan. 1, 1991. Unfortunately, however, theapplicability of autofluorescence techniques has traditionally beenlimited to external areas of the body, or those accessible by endoscopicprobe, thereby making this technique ineffective for diagnosing diseasesof the central portion (jejunum) of the small intestine. See also U.S.Pat. No. 5,827,190, “Endoscope Having an Integrated CCD Sensor”.

In summary, endoscopic inspection is arguably the most efficient andeffective prior art method of diagnosing conditions of the intestinaltract, especially those of a more chronic and insidious nature. However,due to its limited reach, endoscopic inspection is not an option fordiagnosing or treating the central portions of the digestive tract,specifically the central region of the small intestine.

Delivery of Pharmaceutical or Other Agents

Oral administration is perhaps the most desirable approach fordelivering an antigen or pharmaceutically active agent to a livingsubject. This approach, however, suffers from the significant disabilityrelating to the generally poor uptake of antigens or pharmaceuticallyactive agents by the intestinal tract. Some compounds are not suited fororal administration due to their poor penetration into the blood streamof the subject. Additionally, some orally administered agents may bedestroyed through exposure to various substances present in thegastrointestinal system, such as proteolytic enzymes. The digestiveprocess involves the physical and chemical breakdown of ingested food,followed by selective absorption of digested molecules in the intestine.Protease, lipases and other hydrolases secreted into the intestineeffect the chemical breakdown of proteins, carbohydrates and otherlarger molecules present in food, and may also effect the operation orproperties of administered agents.

So-called “controlled release” systems for delivery of agents have beendeveloped to counter some of the foregoing problems with oraladministration. Such systems are typically designed to administer drugsin specific areas of the body, such as the small intestine whereabsorption is comparatively good. In the intestinal tract it is criticalthat the agent not be carried beyond the site of delivery, or otherwiseeliminated before it can exert pass into the bloodstream or exert thedesired topical effect. In many cases, if a delivery vehicle can be madeto couple itself to the lining of the appropriate viscus, its associatedagent will be delivered to the targeted tissue, generally as a functionof proximity and duration of the contact. Such functional relationshipis especially true of radioisotopes.

Another current method of targeting drugs in the gastrointestinal tractinvolves the uncomfortable, time-consuming and often expensive method ofintubation, in which a long, flexible tube containing the drug fordelivery is literally snaked into the intestine of the subject.

Most pharmaceuticals or drugs are specific, in that they are recognizedby key molecules which are involved in the disease. These drugs are thenable to act directly on their relevant targets. For other diseases, suchas cancer and inflammatory diseases, drug molecules are much lessspecific, and considerable often undesirable side effects are seen withthese drugs. Hence, if these agents could be delivered to a specificlocation within the intestine, such diseases could potentially betreated more effectively with reduced side effects.

For tumorous tissue, it has been demonstrated that particles coated witha surfactant show prolonged circulation time after intravenousadministration, and selectively accumulate in tumors because ofcomparatively high tumor vasculature leakage. These circulatingsurfactant-coated particles avoid rapid clearance by reticuloendothelialsystem. This technique of delivery to tumors is commonly referred to as“passive”.

Conversely, so-called “active” delivery is based on attachment ofcirculating particles to antibodies directed against antigens associatedwith the tumor vasculature. These antibodies (and other molecules,including short peptide sequences) can be used for targeting anti-cancerdrugs in living subjects having tumorous tissue.

Receptors and Ligands

The interaction between a drug molecule and its receptor is oftencomplex, and relates to the chemical mechanisms of drug action. Drugmolecules attach (frequently in a reversible manner) to their receptors,not at a single site or by a single type of interaction, but rather in avariety of chemical modes with a number of complementary sites on thereceptor molecule. Interactions that can be involved include relativelystrong forces such as covalent bonding (comparatively rare), hydrogenbonding, or ion-ion interactions, and/or much weaker forces such asion-dipole interactions, dipole-dipole interactions, charge-transfercomplexation, van der Waals interactions, and hydrophobic bonding. Theweaker attractive forces are often of most significance in drug-receptorinteractions. Although individually weak, in the aggregate they providea strong attachment of the drug to the receptor.

Most human immune system cells are white blood cells, of which there aremany types. Lymphocytes are one type of white blood cell, and two majorclasses of lymphocytes are T cells and B cells. T cells are immunesystem cells that help to destroy infected cells, and coordinate theoverall immune response. As is well known, the T cell includes amolecule on its surface known as the T-cell receptor. This receptorinteracts with, inter alia, molecules called MHC (majorhistocompatibility complex). MHC molecules are disposed on the surfacesof many other cells of the body, and help the T cell to recognizeantigen fragments present in its environment. B cells are best known formaking antibodies which bind to an antigen, and marks the antigen fordestruction by other immune system cells. In auto-immune dysfunction,the healthy, viable cells of the subject (as opposed to invadingantigens) are marked for destruction. Hence, if receptor sites orantibody markers can be properly manipulated through the introduction ofspecially designed molecules (such as via the probe of the presentinvention), the defective auto-immune response may be at least partiallyblocked.

The gastrointestinal tract is lined with a single layer of epithelialcells (the mucosa, or epithelium). In the intestine, this layer protectsa highly convoluted surface of projections into the lumen of the smallintestine, and crypts, which penetrate into the underlying connectivetissue. The epithelium is a particularly attractive site for certaintypes of therapy (e.g., gene therapy) because of its large mass of cellsand its relative ease of access via the intestinal lumen. The lumenalsurface of the epithelium interfaces with the external milieu, whereasits basolateral surface interfaces with the internal milieu. Hence, theepithelium may receive nucleic acids applied externally (via the lumen)and to direct the protein or peptide products to, inter alia, theluminal surface (such as for correcting a defect of digestion orabsorption) or to the basolateral surface for secretion into thecirculatory system (so as to act systemically).

The surface area of the intestinal epithelium is greatly increased bythe presence of long, projections known as villi. Villi are microscopic,hairlike, thin-walled structures that contain many small blood vessels.There are large numbers of villi per square inch of intestine and, as aresult, the total surface area of the inner wall of the small intestineis increased several hundred times. The physiological function of thevilli is to facilitate absorption of dietary components that havehydrophilic and lipophilic properties that do not favor passivediffusion processes. Villi serve the same purpose in the case ofnegatively charged (drug) molecules: The large surface area created bythe villi permits a large total absorption of hydrophilic molecules thathave a poor diffusion tendency.

Additionally, the intestine has substantial length. This means there isa very large mass of tissue available for gene transfer. Moreover, thelongitudinal character offers a high degree of precision with respect tothe dosing of an introduced gene. The present invention provides amethod for the in vivo targeting of the intestinal epithelium for theintroduction of nucleic acids.

It has been known for some time that a number of specific uptakemechanisms exist in the intestinal tract for the intake of molecules.Thus, there are specific uptake mechanisms for a variety of differentmolecules. Most of these uptake mechanisms depend upon the presence of aspecific protein or enzyme situated in the mucosal lamina which binds tothe molecule and transports it into the cells lining and lamina. Incertain cases, however, a specific binding protein is released into theintestine, which binds to its ligand in the lumen of the intestine. Forexample, during iron uptake in the intestine transferring is releasedfrom the stomach, binds to iron and is in turn bound by a receptor onthe duodenal mucosa. The receptor-iron-iron complex is then taken up byreceptor mediated endocytosis.

Despite the foregoing techniques, no existing prior art approachpresently provides the ability to deliver pharmaceuticals, ligands, orother therapy agents directly to the central regions of the smallintestine, without surgical intervention.

Tissue Ablation

Anatomical organs, such as the intestine, can develop a variety ofabnormal conditions. It is known to treat such abnormal organ conditionsin more severe cases by removal of the affected portion of theintestine. However, removal of even a portion of the intestine requiresinvasive surgery and general anesthesia, as well as a long recoveryperiod. Other deleterious side effects (such as stomata) generallyaccompany such surgery, thus making such procedures highly undesirablefrom the perspective of the patient.

Alternatively, tissue may be ablated by heating the tissue (thermalablation), freezing the tissue (cryogenic ablation), mechanicallyscraping or cutting of the tissue, or otherwise applying energy ormanipulation of the tissue. The terms “ablating” and “ablation” as usedherein broadly refer to the destruction, removal, or alteration, oftissue or the function of tissue, such as through cauterization,coagulation, scalloping, necrosing, removal, or the like. Ablation ismost frequently accomplished by introducing an ablating member to anarea or volume in proximity to the damaged tissue. Thermal ablationdevices utilize a variety of ablation techniques including laser (i.e.,coherent electromagnetic) energy, RF energy such a millimeter waves,radiation such as alpha and beta particles or gamma rays, anelectrically resistive coil, or any other method of delivering energy.

Lasers are one of the most common devices used for surgical ablation.Lasers are inherently focused to a small area, However, laser energy (aswell as other thermal and cryogenic devices) must be carefully appliedand controlled to ensure that the abnormal tissue is ablated withoutdamaging other normal tissue or organs in proximity to the targettissue.

Typically, large laser radiation sources, such as a Nd:YAG laser or aCO₂ laser, have been coupled to a mobile hand-held device (“laserscalpel”) by means of fiber optic cabling. Thus, by correctlyorientating the scalpel, the light generated by the laser generator isapplied to the desired area. The use of such large lasers, however,suffers from several deficiencies. One such deficiency is size of thelaser energy source, and the requirement that it be physicallypositioned within a fairly short distance from the scalpel so as tominimize problems with the fiber optic coupling. Additionally, suchlasers inherently inefficient in comparison to semiconductor laserdiodes.

Accordingly, most ablation techniques relating to intestinal tissue useendoscopes or other such devices to (i) inspect the condition of thetissue, and (ii) control the application of energy to the damagedtissue. However, as with other endoscopic techniques, ablation of theintestine is limited to those areas reasonably within reach of theendoscope. In cases where ablation of the central portion of the smallintestine is required, the prior art provides no suitable approach shortof invasive surgery.

Radiation Therapy

Typical prior art ionizing radiation treatment (such as for cancer orother malignant lesions) utilizes gamma or X-ray radiation to inducemolecular-level damage within the cancerous or malignant tissue cellnuclei to ablate and effectively kill such cells and/or thwart theirfurther reproduction. Existing radiation delivery systems include anexternal gamma/X-ray radiation source, or in certain cases, use of aradioisotope introduced by injection into the tissue or introducedintravenously, or other vehicle which is swallowed by or introducedendoscopically into the patient. However, these methods generally havethe substantial drawback of indiscriminately irradiating mass amounts ofundiseased tissue adjacent to the malignant cells. For example, thedeposition profile of highly penetrating forms of radiation such asgamma or X-ray radiation (both forms of electromagnetic radiation withcomparatively high frequencies, and hence energies) can not in manycases be accurately controlled within the human body; hence, there issignificant collateral damage resulting from such external treatments totissue and organs immediately in front of and behind the malignancy inthe radiation line-of-sight. Hence, the use of gamma and/or X-rayradiation generally contributes significantly to whole body dose to thesubject. Furthermore, gamma (and to a lesser degree X-ray) radiation isnot easily collimated or laterally focused due to its highly penetratingnature, relating largely to its high energy photons. Such radiationexhibits a significant “tenth” thickness in most materials, even densematerials such as lead.

For a myriad of reasons including the increase likelihood of adhesionsor perotineal cavity infection, it is also impractical and highlyundesirable to surgically perforate the abdomen wall (via lapriscopy orother such techniques) in order to gain closer access to the intestinefor radiation treatment. Esophogeal and rectal endoscopes of the typewell known in the arts are useful in the localized inspection, biopsy,and treatment of accessible areas of the intestine, but again sufferfrom the inability to reach the central portions (majority) of the smallintestine. Based on the foregoing, an improved method and apparatus foraccurate, localized irradiation of the small intestine, including theinterior regions thereof, is needed.

A more recent approach has been to use “targeted” delivery ofradioisotopes to tumor sites or other areas of the intestine. See forexample, U.S. Pat. No. 5,902,583 entitled “Genetic Induction ofReceptors for Targeted Radiotherapy” issued May 11, 1999, whereinradio-labeled ligand localization comprising transducing the tumor witha gene encoding a membrane expressed protein unique to the tumor isdescribed. Monoclonal antibodies directed to “tumor-associated” antigenson cancer cells, and radioactively labeled peptides able to bind toreceptor positive tumor cells are also available. However, an improvedmethod of administration and localized delivery of such radio-labeledligands, especially to the epithelium of the intestine, is needed.

Ultrasound Imaging

Ultrasound imaging systems are commonplace in the prior art. Duringoperation of these systems, ultrasonic signals, typically on the orderof 250 kHz to 20 MHz, are transmitted into a subject's anatomy wherethey are absorbed, dispersed, refracted and reflected. The reflectedultrasound energy is received at a plurality of transducer elementswhich convert the reflected ultrasound energy back into electronic echosignals via the piezoelectric properties of the transducer. Thesereceived echo signals undergo a process known as beamforming; thisprocess correlates the ultrasound signals into spatially coherent“beams.” Subsequently the processed signals are further analyzed toextract echo and Doppler shift information, and ultimately obtain animage of the subject's targeted anatomy (e.g., tissue, organs, vessels).Such images are represented in any number of common formats, includingthe so-called “B-mode.” A B-mode image is an image in which thebrightness or luminosity of component pixels is adjusted in proportionto a corresponding echo signal strength or other measured parameter. TheB-mode image represents a two dimensional cross-section of the subject'starget area tissue through a transducer's scanning plane. The typicalultrasound B-mode image is formed by scanning the subject's targettissue in a predetermined pattern (e.g., linear, raster, conic, orsector scan) of the patient's target area by the transducer probe. Theindividual images produced by ultrasound imaging systems includediscrete frames. Each frame has a limited field of view due to arelatively narrow region traversed by the transmitted ultrasound energy.As the transducer probe is manipulated along the patient's body surface,each previous image is replaced on the viewing display by a new imagedefined by the current position, and thus field of view, of thetransducer probe. Interposed tissue (i.e., that between the organ ofinterest and the transducer(s)) also adds noise and “clutter” to boththe transmitted and reflected signals, however, thereby reducing theaccuracy of the system, and reducing the minimum spatial resolution ofwhich the system is capable.

Inspection and Diagnosis

Another disability associated with prior art “capsule” based inspectionsystems such as the M2A device manufactured by Given Imaging relates tothe practicalities of viewing the image data derived therefrom.Specifically, several hours worth of data (non-compressed) are typicallygenerated by the device during its traversal of the human intestinaltract. Reviewing this data on a minute-by-minute basis can be very timeconsuming and cost-inefficient for a physician or health care provider,since likely only a very small portion of the data is of anysignificance in a diagnosis. In many cases, disease (e.g., polyps, etc.)is quite localized in nature; hence, the physician must necessarilyanalyze several hours worth of data for potentially only a few minutesof worthwhile information. This disability makes the diagnosis andtreatment process more lengthy than needed, and thereby introducessignificant cost inefficiencies which may actually act as a barrier toadoption or use of the technology in the first place. This is especiallytrue since, in most cases, a highly skilled and qualified physician orexpert is required to analyze the data produced by the probe in order tomake a diagnosis, thereby resulting in either (i) excessive fees forperforming the diagnosis as compared to other prior art treatmentoptions; or (ii) the physician or health care provider absorbing theadditional cost of performing the diagnosis as compared to the otheravailable techniques. On a “dollars per hour” basis, prior art devicessuch as the M2A capsule are very cost inefficient for the physician andhealth care provider, and are generally avoided despite their desirabletechnological features.

Another problem associated with the requirement under the prior art toview all of the visual data obtained from the probe relates to fatigueof the viewer (physician). Specifically, it is known that the quality ofreview will degrade as a function of viewing time, since the viewerinvariably becomes tired or fatigued after extended durations ofviewing. This is particularly true of the viewer's eyes and highercognitive functions. Continuous viewing of several hours of intestinalvisual data, which comparatively speaking has little in the way ofvariation or change, can significantly reduce the physician's acuity andmental/visual faculties. Ideally, the physician could review the data inshorter segments; however, this approach does not address the foregoingissues regarding time efficiency, since the physician must still viewall of the data, whether in segments or as one uninterrupted segment.

Additionally, there is a significant potential drawback associated withviewing multiple segments of data for one patient at different times,namely the reduction in correlation of the data from different segmentsby the viewing physician. Specifically, if the physician views forexample four 60-minute segments of a patient's data on four differentdays, their chance of correlating artifacts or data of interest presentin one segment (such as the presence of diseased tissue, polyps, etc.)to that of another segment, which may be viewed as much as four dayslater in the present example, is potentially reduced. Even when takingnotes, the physician may forget conscious or subconscious informationgleaned from reviewing an earlier segment when viewing a subsequentsegment several days later. Furthermore, the physician may have torefresh their memory by running back all or a portion of the earliersegment(s). The physician may also, when viewing data from multiplepatients over the course of a given week, confuse data associated withone patient with that for another. This effect is even present to alesser degree when viewing the data in contiguous (i.e., uninterrupted)fashion. Hence, there is in effect a “synergy of correlation” associatedwith viewing all of the data for one patient at the same time (or inclose sequence).

Yet a further problem associated with the prior art capsule diagnosistechniques relates to the potential for legal liability associated withthe diagnosis. Specifically, under a medical malpractice theory,physicians and health care providers may expose themselves to potentialliability under various laws if their review of the data generated bythe capsule fails to detect a condition or disease which would normallybe detectable by such means. Hence, if the physician or other diagnosticprofessional “skips over” part of the data in an attempt to reduce thelength of time spent performing the diagnosis (and hence the effectivecost), they are in effect significantly increasing the risk that theywill be sued for medical malpractice. When coupled with theaforementioned cost disincentives, the caregiver is faced with thechoice of (a) reducing their cost efficiency (and hence profit) whileincreasing their risk for a significant malpractice legal action, or (b)continuing to use the prior art technologies which generally do notsuffer from either of these disabilities to anywhere near the samedegree.

Based on the foregoing, it would be highly desirable to provide anapparatus and method by which treatment could be rendered remotely tovarious portions of the intestinal tract. More specifically, it would behighly desirable to provide an apparatus and method for, inter alia, (i)visual, autofluorescent, ultrasonic, or other types of inspection; (ii)delivery of medication, pharmaceuticals, radioisotopes, directradiation; (iii) biopsy; (iv) physical expansion of constricted or scartissues; (v) detection of the presence of one or more molecules presentin vivo; and (vi) selective tissue ablation, in all portions of theinterior of the digestive tract including the small intestine withoutinvasive surgery or other extraordinary and potentially deleteriousmeans.

Furthermore, such improved apparatus and methods would address thebarriers to more widespread adoption of the technology within themedical community, including the high relative cost per evaluation, andthe significantly increased risk for medical malpractice liability.

SUMMARY OF THE INVENTION

The present invention satisfies the aforementioned needs by providing animproved endoscopic device and method of diagnosing and treatingpatients utilizing the same.

In a first aspect of the invention, an endoscopic “smart probe” isdisclosed which operates autonomously of external devices and is sizedand shaped such that it may be introduced into the esophagus andultimately small intestine of the patient undergoingexamination/treatment. The probe traverses the patient's intestinaltract by virtue of normal peristaltic contractions occurring therein. Ina first embodiment, the probe utilizes a miniature sensor such as acharge-coupled device (CCD) camera and a fiber optic/diode illuminationsystem for inspection of the intestine wall. The CCD camera operation issupported by, inter alia, a “flash” analog-to-digital converter (ADC),microcontroller, and an inductive (or capacitive) data transfersub-circuit which facilitates real-time transfer of the acquired imagedata out of the probe to an external monitoring and control device (MCD)in order to provide real-time data analysis and to minimize probe memoryrequirements and size. The MCD incorporates a signal processor,microprocessor, video driver and display, and storage device. Inductivecoupling is utilized as a source of power to the probe to permitoperation of the CCD, ADC, and microcontroller, as well as otherfunctions such as illumination. The probe is completely sealed so as tobe protected against damage by gastric acids or other potentiallydamaging substances residing within the patient.

In a second embodiment, the smart probe of the present invention furtherincludes a miniature package digital signal processor (DSP), and randomaccess memory (RAM) with associated memory controller in addition to theCCD array, ADC, and other components. The DSP provides data formattingand compression functions within the probe to permit storage of discreteamounts of image data within RAM during probe operation without the needto transfer data out of the probe. Accordingly, the probe can operateautonomously of the MCD for greater periods of time, thereby providingthe operator/physician with additional flexibility. Alternatively, theprobe can transfer data out at a faster rate in compressed format. Aflash memory of the DSP may also modified by way of program datatransmitted to the probe via the data transfer sub-circuit.

In another embodiment, a miniature NiMH or comparable battery is used topower the device during its progression through the patient either inconjunction with or in lieu of the aforementioned inductive powertransfer circuit.

In yet another embodiment, the probe includes a fully integrated “systemon a chip” (SoC) application specific integrated circuit (ASIC)incorporating, inter alia, a digital processor core, embedded programand data random access memories, radio frequency (RF) transceivercircuitry (such as a “Bluetooth™” 2.4 GHz transceiver or TM-UWB PPMdevice), modulator, ADC, and analog interface circuitry. The processorcore comprises, inter alia, an extensible RISC processor which is userconfigurable with respect to a set of predetermined extensioninstructions specifically adapted to various processing tasks associatedwith various embodiments of the probe, such as (visual) imageprocessing, autofluorescense imaging and analysis, ultrasonic signalprocessing, and the like. Such user-customizable, optimized extensibleprocessor cores advantageously have a reduced gate count require lesssilicon, and consume less power than comparable non-optimized cores.Accordingly, the manufacturer or designer may select the appropriateoptimized core configuration and instruction set applicable to theanticipated use of the probe, thereby reducing the required space neededwithin the probe to accommodate the ASIC, and the power consumedthereby. Additionally, the core (and in fact the entire SoC device)optionally includes one or more processor “sleep” modes which allowportions of the core and/or peripherals to be shut down during periodsof non-operation in order to further conserve power within the deviceand reduce heat generation.

In yet another embodiment, the imaging array comprises an infrared (IR)imaging sensor array adapted to receive thermal energy (infrared-bandelectromagnetic radiation) radiated by the intestine wall tissue.

In a second aspect of the invention, an endoscopic smart probe isdisclosed which is useful for autofluorescence analysis of theintestinal tract of a patient. In one embodiment, the smart probeincorporates a miniature semiconductor (diode) laser tuned to emitcoherent light energy in the desired autofluorescence band. Acomplementary CCD array is used to detect the fluorescent energyradiated by the surrounding intestinal tissue during or after excitationby the laser energy. The charge accumulated on the CCD cells is thenamplified and converted to a digital format for further processing andanalysis as previously described with respect to the first aspect of theinvention. In another embodiment, both visual and autofluorescenceimaging capability are included within a single smart probe.

In yet another embodiment, the laser diode and associated circuitry andpower supply are adapted to ablate intestinal tissue through directirradiation with coherent electromagnetic energy.

In a third aspect of the invention, an improved endoscopic device usefulfor implanting the aforementioned endoscopic smart probe is disclosed.The device utilizes a probe housing which retains the smart probe duringinsertion of the device tip into the patient, yet which also allowsremote expulsion of the probe from the device into the patient whendesired by the operator. In one embodiment, the probe is expelled by airor fluidic pressure transmitted down the length of the device; arupturable closure or diaphragm is used to protect the probe duringinsertion.

In a fourth aspect of the invention, a method for inspecting and/ortreating the interior regions of the intestinal tract using theaforementioned smart probe is disclosed. The probe is introducedendoscopically as described above (or orally), and monitored via thedata transfer circuit previously described, thereby providing real-timevisual and/or autofluorescense imaging of the interior surfaces of theintestinal as the probe traverses the intestinal tract. Alternatively,the probe may be deployed within the patient, activated to obtain datafor one or more periods, and then analyzed after expulsion from thepatient.

In a fifth aspect of the invention, an improved apparatus and method fordelivery of radionuclides to diseased tissue within the intestinal tractof a living subject are disclosed. In one exemplary embodiment, theapparatus comprises the foregoing “smart” probe which has been furtheradapted to carry and expose a radioactive source at a prescribedlocation within the intestine. The source can comprise a gamma, beta,alpha, and/or even neutron emitting material which is shielded by aretractable shield. The retraction of the shield is controlled via theon-probe processor or microcontroller, or alternatively via anexternally generated signal.

In a second embodiment, a plurality of ligands “tagged” withradionuclides are carried within a repository or container within theprobe until the desired location within the intestinal tract is reached.Under either internal or external control, the probe deploys the ligandssuch that the ligands are deposited on the intestine wall structuressuch as, for example, the villi of the small intestine. Receptor siteson the tumor cell membrane or other affected locations within theintestinal wall, which are specifically targeted by the ligands, receivethe tagged ligands, which then proceed to ionize tumor cell material viaemitted beta, alpha, gamma, or neutron radiation until decay orevacuation of the radionuclide.

In a third embodiment, the probe is adapted to contain a plurality ofnanostructures (e.g., C₆₀ fullerenes, also known as “Buckyballs”) whicheach include one or more “captured” atoms or molecules of a desiredradionuclide within the cavity of the nanostructure. The nanostructuresare implanted into the interior wall (such as the villi) of thesubject's intestine in the localized region of the diseased tissue ortumor and absorbed at least partially thereby either by passivediffusion or other mechanisms. In one variant, the radionuclide heldwithin the fullerene is chosen to have a very short half-life so as tomitigate unwanted exposure to non-diseased tissue after absorption ofthe fullerenes into the intestine wall.

In a sixth aspect of the invention, an improved apparatus and method fordelivering chemical or biological agents (such as ligands, medication,microspheres, contrast agents, or even liquid radionuclides) isdisclosed. The apparatus generally comprises an endoscopic smart probehaving at least one reservoirs containing at least one chemical orbiological agent, the agent being selectively releasable from thereservoir(s). In one exemplary embodiment, the apparatus comprises asmart probe configured with an etched substrate element having one ormore reservoirs with permeable or controlled release coverings (caps).The release of the medication occurs through (i) the predetermineddisintegration or dissolution of the caps; (ii) permeation or diffusionthrough the caps; and/or (iii) controlled dissolution of the capmaterial, such as through the application of an electrical current.

In a second exemplary embodiment, one or more molecules of thechemical/biological agent are disposed within the cavities ofnanostructures, the nanostructures being carried within a repository inor on the probe. The nanostructures are released at a desired locationand subsequently absorbed into or diffused through the tissue wall,thereby ultimately delivering the molecules of medication directly tothe desired location(s).

In seventh aspect of the invention, an improved method of medication orligand delivery within a living subject via nanostructure structures isdisclosed. The method generally comprises providing at least onemolecule within a nanostructure structure; disposing said nanostructurestructure (and molecule) within an autonomous probe; disposing saidprobe in vivo, such as in the intestinal tract of the subject, anddepositing the nanostructure structure at a desired location in vivo. Inone exemplary embodiment, the molecule is a ligand targeted for specificreceptor sites on a tumorous entity within the subject's smallintestine, and the nanostructure comprises a Carbon-60 “fullerene”structure. Upon deposition of the fullerene(s) in the region of thetumor cells, the ligand is received by the targeted receptor, thefullerene “cage” effectively intact and acting to protect the ligandfrom other potentially degrading or interfering processes.

In another exemplary embodiment, one or more specially selectedpolymerized molecules are disposed within the cavity of thenanostructure structure such that the polymerized molecule(s) is/arecaptured therein. The polymerized molecule(s) may comprise, for example,a grouping of ligands, or a ligand with a co-associated “retainer”molecule. Upon introduction of the structure in vivo, the polymerizedmolecule(s) are depolymerized or otherwise, thereby allowing selectedcomponents of the molecule(s) to be extracted or released from thenanostructure. These released components are then diffused, received bycomplementary receptors, or otherwise absorbed by the targeted tissue inthe subject. Alternatively, a ligand is disposed externally to thefullerene cage, thereby allowing bonding to a receptor site with thefully polymerized molecule intact. In one variant, the polymerizedligand and associated fullerene/retainer molecule is sufficientlyunstable that the ligand is “torn” from the fullerene/retainer, therebyallowing the ligand to remain disposed on the receptor.

In yet another exemplary embodiment, “nanotubes” are formed whichcontain one or more molecules for delivery to the subject. In onevariant, the nanotubes contain ligands targeted to one or more receptorson a tumor. The nanotubes are disposed within solution in a reservoir ofthe smart probe such that they may be selectively released at a desiredlocation, such as at the site of the tumor within the subject'sintestine. Upon exposure to acids in intestinal tract (after releasefrom the probe), the nanotubes preferentially degrade at their taperedends and release their internal molecules (e.g., targeted ligands).Alternatively, the active portion of the ligand is disposed in a freeend of the nanotube, such that the ligand may be readily received by thetargeted receptor on the tumor cells. In yet another variant, thenanotubes are disposed in an array, ligand-side out, such that theligands may be readily extracted from the nanotubes upon reception bythe targeted receptors.

In an eighth aspect of the invention, an improved apparatus and methodfor obtaining a biopsy of the intestinal wall of the subject aredisclosed. In one exemplary embodiment, the apparatus includes at leastone selectively controlled aperture and associated reservoir disposed inthe outer region of the probe. Upon the probe reaching the desiredlocation within the subject's intestine, the aperture is selectivelyopened, thereby exposing the reservoir beneath. Intestinal tissueprotruding through the aperture due to, inter alia, surface tension, isexcised by closing the aperture shutter, the excised tissue beingretained within the reservoir until the probe is expelled from thesubject, at which point the excised biopsy may be examined using anynumber of well known techniques. In another embodiment, one or moreselectively controllable “scoops” disposed on the surface of the probeare provided which, when activated, collect tissue cells as the probetraverses the intestine.

In a ninth aspect of the invention, an improved apparatus and method fortreating constrictions, obstructions (or adhesions occurring between theinterior surfaces of the intestine wall) of the intestinal tract aredisclosed. In one exemplary embodiment, the apparatus comprises thesmart probe of the invention having a reduced radius and being equippedwith an inflatable element which expands the effective radius of theprobe in at least a portion of its cross-section, thereby simultaneouslyexpanding the surrounding intestinal tissue. In one variant, the probeincludes a pressurized gas reservoir (e.g., “trailer”) which acts as asource of potential energy for the inflatable element upon activation,thereby minimizing the electrical power requirements of the device.

In another embodiment, the trailer acts as a reservoir for the probe fordispensing chemical or biological agents, microspheres, fullerenes,nanotubes, or the like, as previously described.

In yet another embodiment of the apparatus, the probe comprises amicro-solenoid assembly with a cam-like structure which, based on theapplication of electrical current through the solenoid, permits aportion of the probe to expand (and subsequently contract) under commandof the probe's microcontroller or other external signal.

In a first embodiment, the method of treating generally comprises firstdisposing the probe within the intestine of the subject proximate theconstriction; and causing the probe to expand in radius or otherwisedeform its shape so as to expand at least a portion of the constriction.In one exemplary variant of the method, the probe is tracked usingconventional X-ray techniques such that its proximity to theconstriction can be accurately determined. When properly positioned, theprobe is expanded within the constriction as required to at leastpartially relax the constriction. In another variant, the probe locationis tracked via a radio frequency, ultrasonic, or other tracking signalemitted from the probe. In yet another variant, a piezoelectrictransducer element disposed on the probe (described below) is used toacoustically determine the proximity of the probe to theconstriction/obstruction. In yet another variant, the CCD or MOS imagingarray is used to optically (visually) determine the proximity of theprobe to the constriction/obstruction.

In a second embodiment, the method comprises disposing the probe withinthe intestine of the subject proximate the constriction; and causing theprobe to release one or more chemical substances or electrical charge soas to induce expansion or contraction of at least a portion of theconstriction.

In a tenth aspect of the invention, an improved smart probe having a“smart” housing and electronics configuration is disclosed. Portions ofthe housing are fabricated from a multi-layer laminatedsemiconducting/conducting carbon fiber polymer matrix which integratesthe functionality of one or more components within the housing itself,thereby obviating the need for separate, discrete components whichconsume additional space within the probe. In one embodiment, asemiconductor laser is formed within the housing itself, thesemiconductive region of the device having bandgap energy in the rangeof approximately 0.1-2 eV, and being used to generate the desiredwavelength of light for autofluorescense or infrared analysis of thetissue within the subject's intestine.

In another embodiment, at least a portion of the smart housing is usedas “battery” for the storage of electrical energy used by the probe whendeployed in vivo. The housing is constructed in two or more polarizedfiber/matrix layers which form a capacitive element capable of storingelectrical charge.

In yet another embodiment, the housing includes one or morepiezoelectric transducers adapted to sense pressure variations on theouter surface of the housing, such as would result from peristalticcontractions of the subject's intestine. The transducer(s) produce anelectrical signal related to the pressure applied thereto, the signalbeing converted to a digital representation for analysis either on-probeby the digital processor (if so equipped), or off-probe.

In an eleventh aspect of the invention, an improved apparatus and methodfor obtaining acoustic images using an autonomous endoscopic smart probeare described. In one embodiment, the apparatus comprises a smart probehaving an piezoelectric transducer (e.g., “ceramic”) adapted to transmitand receive ultrasonic acoustic waves. Processing of the acousticsignals may be performed “on probe” using optimized algorithms withinthe probe's digital signal processor, or alternatively raw data isstreamed from the probe to a sensor disposed external to the subjectusing a wireless communications link, and subsequently analyzed “offprobe”.

In a twelfth aspect of the invention, an improved apparatus and methodfor detecting the presence of certain substances or antigens isdisclosed. In one embodiment, the apparatus comprises a sensing arraydisposed at or near the surface of the probe. The sensing array isexposed to the tissue of the intestine wall, allowing the sensing arrayto detect the presence of certain substances. In one variant, the sensorcomprises a plurality of molecular receptor sites which are configuredto receive only one target molecule (or class of molecules). The sensingarray is selectively exposed at the desired location within theintestinal tract, and then subsequently covered to avoid furthercontamination of the array during the remaining length of the intestine.After expulsion, the sensor array is examined to determine the presenceof any of the target molecule within the area of array exposure withinthe intestine.

In another embodiment, electrical conductivity (or alternativelyresistivity) is measured across a membrane or other device; the presenceof target molecules (analytes) is reflected in changes in theconductivity due to, inter alia, ion diffusion. In yet anotherembodiment, the detection of the target molecules is performed using abioelectronic sensor comprising a thin, electrically conductivesurfactant polymeric layer to which members, (e.g., receptors) ofspecific binding pairs are bound.

In yet another embodiment, electrical conductivity (or resistivity) ismeasured across at least one discontinuous “bridge” of receptormolecules disposed between inorganic conductor terminals. When thebridge is completed via the reception of the target molecule(s), theelectrical conductivity increases (or conversely, the resistancedecreases) due to outer shell electron transfer across the targetmolecule(s) and receptor(s). The conductivity increase (or resistancedecrease) is detected by conductivity circuitry within the probe. In onesub-variant, a plurality of parallel bridge circuits are provided, andcoincidence logic is used to help avoid detection of “false positives”.The sensitivity of the device to detecting the target molecule(s) isalso increased. The organic receptor molecules may also be bounddirectly to certain inorganic materials of the probe or sensing array,thereby enhancing the conductivity of the receptor/conductor junction.

In another aspect of the invention, the aforementioned smart probe(“primary” probe) is used to deploy one or more special functionsecondary probes within the subject's intestinal tract, the specialfunction probes being adapted to perform a variety of therapeutic oranalytical functions such as irradiation of a portion of the subject'sintestine, expansion of the intestinal wall, timed release of ligands orother pharmaceuticals, etc. In one exemplary embodiment, the primarysmart probe includes a “trailer” probe which is selectively separablefrom the primary probe by the operator or upon the occurrence of apredetermined condition or set of conditions. The trailer probe isfurther equipped to subsequently expand and/or “wedge” itself within theintestine, such that it remains effectively stationary for a period oftime while the primary probe continues down the intestinal tract viaperistalsis. The therapy agent (such as, for example, a radionuclidesource) is disposed within the trailer, thereby allowing the extendedapplication of the therapeutic action to the desired intestinal tissue.Upon command from the operator and/or the occurrence of a predeterminedevent, the trailer probe alters its shape/configuration (e.g.,deflates), thereby allowing it to subsequently proceed down theintestinal tract via peristalsis. In one variant, the trailer probecomprises a microchip pharmaceutical delivery device adapted forcontrolled release of pharmaceuticals or other agents to a localizedregion of the intestine for an extended period.

In a fourteenth aspect of the invention, improved apparatus and methodsfor enhancing the efficiency of diagnosis of the intestinal tract of thesubject, as well as for on-probe/off-probe processing, are disclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a representation of the human digestive tract, illustratingthe locations and typical extent of prior art endoscopic andcolonoscopic inspection techniques.

FIG. 2 is a typical autofluorescence spectrum of intestinal tissueillustrating the difference in response for normal and diseased tissuebased on exposure to light at a is wavelength in the range of 450 to 700nm.

FIG. 3 is a perspective view of a first embodiment of the smart probe ofthe present invention.

FIG. 4 is a front view of the smart probe of FIG. 3 illustrating thearrangement of the lenses and the CCD array.

FIG. 5 is a cross-sectional view of the smart probe of FIG. 3 takenalong line 5-5, showing the internal arrangement of components therein.

FIG. 5 a is a cross-sectional view of the smart probe of FIG. 3 takenalong line 5 a-5 a, further showing the internal arrangement ofcomponents therein

FIG. 6 is a block diagram of one preferred embodiment of the dataacquisition, processing, storage, and transfer circuitry of the smartprobe of FIG. 3.

FIG. 7 is a block diagram of one preferred embodiment of an inductivepower transfer circuit used in the smart probe of FIG. 3.

FIG. 8 is a perspective view of one embodiment of the MCD and itsassociated remote unit according to the present invention.

FIG. 9 is a block diagram illustrating the data processing and powertransfer components of the MCD and its associated remote unit.

FIGS. 10 a and 10 b are perspective and front views, respectively, of asecond embodiment of the smart probe of the present invention.

FIG. 11 is a cross-sectional view of the smart probe of FIG. 10 a, takenalong line 11-11.

FIG. 12 is a block diagram of one preferred embodiment of the dataacquisition, processing, storage, and transfer circuitry of the smartprobe of FIG. 10.

FIG. 13 a is a cross-sectional view of a first embodiment of an improvedendoscopic delivery device capable of implanting the smart probe of thepresent invention within the intestinal tract of a patient.

FIG. 13 b is a elevated plan view of the closure of the delivery deviceof FIG. 13 a.

FIG. 14 is a cross-sectional view of second embodiment of an improvedendoscopic delivery device capable of implanting the smart probe of thepresent invention within the intestinal tract of a patient.

FIG. 15 is flow diagram illustrating one embodiment of the method ofdiagnosing and/or treating the intestinal tract of a patient using thesmart probe of the present invention.

FIG. 16 is a side plan view of one exemplary embodiment of the smartprobe of the present invention, illustrating relative location of theSoC device.

FIG. 16 a is a block diagram illustrating the various functionalcomponents of the SoC device of FIG. 16.

FIG. 16 b is a block diagram illustrating the various functionalcomponents of another embodiment of the SoC device of the inventionincorporating a TM-UWB transceiver.

FIG. 17 is a functional block diagram illustrating the operation of theSoC device of FIGS. 16-16 a, including interaction with a remote tagreader.

FIG. 18 a is a partial perspective view of one exemplary embodiment ofthe smart probe of the invention equipped with ionizing radiation sourceand shield element(s).

FIG. 18 b is a partial cross-sectional view of the probe of FIG. 18 ataken along line 18 b-18 b illustrating the internal components thereof.

FIGS. 18 c and 18 d are partial perspective views of one embodiment ofthe track and ball assembly of the smart probe of FIG. 18 a.

FIG. 18 e is a partial cross-sectional view of the probe of FIG. 18 ataken along line 18 e-18 e illustrating various components of the shieldassembly.

FIG. 18 f is a front plan view of one embodiment of the radiation sourceand shield elements, illustrating the relative radiation emissionpatterns from the probe.

FIG. 18 g is a perspective view of the radiation source and shieldelements of FIG. 18 f, illustrating the relative radiation emissionpatterns from the probe.

FIG. 18 h is a plan view of another embodiment of the radiation sourceof the invention, illustrating the use of sectored radiation sourceelements therein.

FIG. 19 a is a partial cross-section of one exemplary embodiment of thesmart probe of the invention, incorporating a fluid (e.g., ligandsolution) reservoir an pressurized gas chamber therein.

FIG. 19 b is a partial cross-section of the probe of FIG. 19 a,illustrating one of the apertures utilized therein and its associateddislocatable diaphragm element.

FIG. 19 c is a partial cross-section of another embodiment of the probeaperture and seal of the invention, wherein the fluid ejection isgenerally oblique to the epithelium.

FIG. 20 is a partial cross-sectional view of the probe of FIG. 19 a,illustrating the ejection of fluid from the probe while in vivo.

FIG. 20 a is a graphical representation of a carbon-based fullerenestructure with “caged” payload.

FIG. 21 is a logical flow diagram illustrating the general methodologyof utilizing nanostructures to deliver radionuclide dose via theintestinal tract using the smart probe of the invention.

FIG. 22 is a cross-sectional diagram illustrating another embodiment ofthe invention, wherein a carbon nanotube is used in conjunction with anactivated molecule and payload molecule for delivery of the payload tothe intestinal tract.

FIGS. 23 a-23 d are various views of one exemplary embodiment of thesmart probe of the invention, configured for tissue biopsy within theintestinal tract.

FIGS. 24 a-24 b are cross-sectional and perspective views, respectively,of another embodiment of the smart probe of the invention adapted fortissue biopsy.

FIGS. 25 a-25 d are various views of yet another embodiment of the smartprobe of the invention configured for in vivo expansion of theintestine.

FIG. 26 is a logical flow diagram of one embodiment of the generalmethodology for relieving constrictions within the intestine utilizingthe probe of FIGS. 25 a-25 d.

FIG. 27 a is a perspective view of yet another embodiment of the smartprobe of the invention, wherein the probe includes a structuralelectronics housing having an intrinsic capacitor energy storage device.

FIG. 27 b is a composite view of a portion of the housing of the probeof FIG. 27 a, illustrating the carbon composite matrix and theelectrical properties thereof.

FIG. 27 c is a cross-sectional view of the probe of FIG. 27 a,illustrating the relationship of various components therein.

FIG. 27 d is a logical flow diagram illustrating one embodiment of themethodology of manufacturing the structural probe housing of FIGS. 27a-c.

FIG. 28 is a cross-section of yet another embodiment of the smart probeof the invention employing structural semiconductive device(s) therein.

FIG. 29 is a perspective view of yet another embodiment of the smartprobe of the invention, adapted for pressure measurement within theintestinal tract.

FIG. 30 is a cross-sectional view of the probe of FIG. 29, illustratingthe various components therein.

FIG. 30 a is a functional block diagram illustrating the electronicprocessing of the pressure signal performed by the probe of FIG. 30.

FIG. 31 a is a perspective view of yet another embodiment of the probeof the invention, including 2-D phased ultrasonic transducer array andtransmit/receive beams.

FIG. 31 b is a front plan view of the transducer array of the probe ofFIG. 31 a, illustrating the relationship of the various transducerelements therein.

FIG. 31 c is a side perspective view of the 2-D transducer array ofFIGS. 31 a-31 b, illustrating the construction thereof.

FIG. 31 d is a block diagram of the electronic functions associated withthe 2-D array of the probe of FIG. 31 a.

FIG. 31 e is a partial schematic of an exemplary transmit/receivebeamformer device of the circuit of FIG. 31 d.

FIG. 31 f is a schematic of one exemplary embodiment of the amplifierassembly of the beamformer circuit of FIG. 31 e.

FIG. 31 g is a functional block diagram illustrating the relationship ofthe electronic components of the probe of FIG. 31 a, including processorcore, memory, T/R switch, and RF transceiver/modulator.

FIG. 32 is a perspective view of one exemplary embodiment of the smartprobe of the invention having detection arrays adapted to detect thepresence of one or more molecular species.

FIG. 32 a is logical flow diagram illustrating one exemplary embodimentof the method of detecting molecular compound(s) utilizing the probe ofFIG. 32.

FIG. 33 is a partial schematic of one exemplary embodiment of themolecule detection circuit of the probe of FIG. 32.

FIG. 33 a is a schematic of exemplary gate logic used to implement thecoincidence functionality of the probe of FIG. 32.

FIGS. 34 a-34 b are side and front cross-sectional views, respectively,of one exemplary embodiment of the smart probe of the inventionincluding microwave ablation target with resonant cavity.

FIG. 35 is functional block diagram illustrating one exemplaryembodiment of the data processing apparatus of the present invention.

FIG. 35 a is a graphical representation of an exemplary multi-portionscreen display utilized by the apparatus of FIG. 35.

FIG. 35 b is a graphical representation of an exemplary data packetprotocol used with the system of FIG. 35.

FIG. 36 a is a graphical representation of typical endoscopic probe dataindicating the presence of an intestinal polyp.

FIG. 36 b is a graphical representation of typical endoscopic probe dataindicating normal tissue.

FIG. 36 c is a graphical representation of typical endoscopic probe dataindicating the presence of a partial occlusion or adhesion.

FIG. 36 d is a graphical representation of the intestinal polyp of FIG.36 a, illustrating the feature identification and curve-fittingmethodology of the invention.

FIG. 36 e is a graphical representation of the parametric identificationprocess used to characterize features such as the polyp of FIG. 36 d.

FIG. 36 f is a graphical representation of an exemplary feature packetprotocol used with the system of FIG. 35.

FIG. 37 is a logical flow diagram illustrating one exemplary embodimentof the generalized methodology for on-probe/off-probe data processingaccording to the invention.

DETAILED DESCRIPTION OF THE INVENTION

Reference is now made to the drawings wherein like numerals refer tolike parts throughout.

As used herein, the term “autonomously” shall mean independent of directphysical or tactile control by an operator or external device. As willbe described in greater detail below, the smart probe of the presentinvention is designed to be initially introduced into the patient afterwhich time the probe operates autonomously; i.e., only utilizingelectrical, inductive, magnetic, or radio frequency signals to enable orperform certain desired functions, with no direct external physicalcontact or connections. This is to be distinguished from prior artendoscopic inspection or treatment devices, which always maintain somephysical or tactile link (such a tube, electrical wire, or fiber opticbundle) with the operator, and hence which do not operate autonomouslywhile in the patient.

The term “ionizing radiation” as used herein refers to any form ofradiation, whether particulate or wave-like in nature, which hassufficient energy to remove an electron or other particle from an atomor molecule, thus producing an ion and a free electron or otherparticle. Examples of ionizing radiation include, but are not limitedto, gamma rays, X-rays, protons, positrons, electrons, and alphaparticles.

The term “polymer” and “polymerization” shall mean any molecule whichforms one or more structures or linkages (which may be repeating) suchthat a larger, composite molecule is produced. Similarly, the term“depolymerization” shall mean any process whereby the foregoingstructures or linkages are dissolved or broken.

The term “fullerene” as used herein shall mean not only C60 (i.e., thecommon buckminster-fullerene) but also the higher molecular weightfullerenes (e.g., C70, C84 . . . C240) and also their derivatives,regardless of shape.

The term “nanostructure” shall mean the aforementioned fullerenes, aswell as nanotubes and any other discrete nanometer-scale carbonstructure having a plurality of atoms.

The term “agent” shall mean any antigen or compound, pharmaceutical orotherwise, introduced in vivo to produce at least one desired result.

The term “ligand” as used herein shall mean any atom, radical, ion, ormolecule in a complex (polyatomic) group which is bound to a centralatom.

The term “receptor” shall mean any protein or other molecule whichreceives or binds to one or more specific types of target molecules oratoms.

The term “imaging” or “imaging sensor” or “imaging array” shall mean anydevice adapted to receive energy of a certain type including, withoutlimitation, electromagnetic energy or particulate radiation.

As used herein, the term “numerical aperture” shall mean a measure ofthe capture angle of EMR, including the maximum angle of EMR rays thatwill be reflected down the transfer medium (e.g., fiber) by totalreflection. Numerical aperture (NA) is given by the followingrelationship:NA=sin θ=SQRT(n ₁ ² −n ₂ ²)Where:

n₁=refractive index of core

n₂=refractive index of clad

FIG. 3 is a perspective view of a first embodiment of the smart probe ofthe present invention. The probe 300 comprises an outer housing 302having a generally ellipsoid shape and an inner cavity 303 (not shown),a lens aperture 304 positioned in one end of the housing 302, and lenses306 a, 306 b mounted in alignment with the aperture 304 within a lensretaining board 305. An optional lens cover 308 covers the lenses 306 a,306 b and seals the aperture 304. A plurality of other components(including, inter alia, a CCD or other imaging array, microcontroller,clock, parallel/serial drivers, and sample and hold circuitry, notshown) are disposed within the aforementioned cavity 303 or otherwisewithin the outer housing 302 itself. These other components aredescribed in greater detail below with reference to FIGS. 6-7. Agenerally ellipsoid shape is used for the outer housing 302 of thepresent embodiment to facilitate passage of the probe 300 through theintestinal tract of the patient, and to assist in maintaining the properorientation of the probe during use; e.g., such that the lenses 306 areoriented to have sufficient perspective and focal length to adequatelyview portions of the interior of the patient's intestine. Optionally,the rear portion of the probe 300 may be flared, or other contours ordevices utilized to assist in orientation within the intestine. Whilethe present embodiment utilizes a generally ellipsoid shape for theouter housing 302, it will be recognized that other shapes andconfigurations for the outer housing (and lens aperture 304) may be usedin accordance with the present invention. For example, substantiallycylindrical or “bullet-shaped” outer housings could be used.Alternatively, an outer housing having a non-symmetric lateralcross-section (i.e., that taken in a plane to which the longitudinalaxis of the housing 302 is normal) could be employed. Many othersuitable shapes exist.

Furthermore, it will be recognized that the probe 300 may operate inboth a “forward looking” and “rearward looking” orientation within thepatient. Specifically, the probe may be disposed within the intestinesuch that the aperture 304 (and associated CCD array) is oriented in thedirection of probe advance, or alternatively rearward. As described inmore detail below, it is further contemplated by the present inventionthat the probe may be equipped with both forward and rearward lookingCCD arrays.

The outer housing 302 is sized in the present embodiment to have adiameter (at its widest point, measured across its circumference) on theorder of 12 mm (roughly 0.5 in.) in order to allow unencumbered passagethrough the intestinal tract and even the ileocecal valve. However, itwill be appreciated that other sizes of probe, both smaller and larger,may be used depending on a variety of factors including the size of, andany peculiarities associated with, a given patient's intestines, as wellas the instrumentation/components desired to be carried by the probe300.

The outer housing 302 is in the present embodiment constructed of amechanically rigid and stable polymer such as ethylenetetrafluoroethylene (Tefzel®) which is also resistant to chemicalexposure and other environmental influences, and which is also non-toxicto the patient. Tefzel® also has the desirable property of being able tobe fabricated with a smooth (i.e., low coefficient of friction) surfacewhich further facilitates passage of the probe 300 through theintestinal tract, although this property is not essential. It can beappreciated, however, that other materials (such as certain metals,resins, composites, or even organic materials) may be used to form allor part of the outer housing 302. For example, the housing need not be adiscrete component, but rather may be an encapsulant such as that usedon integrated circuit devices.

The housing 302 is made of minimal wall thickness so as to have adequaterigidity yet permit the maximum size cavity therein. In the presentembodiment, a wall thickness of 0.5 mm (roughly 0.020 in.) is selected,although other values may be used. The outer housing of the probe ofFIG. 3 is split circumferentially at the mid-section to facilitatecomponent insertion and removal. The halves of the housing 302 a, 302 bare fit tightly together so as to minimize the possibility of fluidleaking into the cavity 303. A sealing agent 580 (and/or a sealing ringor gasket) is used to further prevent fluid leakage. Note also that suchsealing is applied around the interface of the lens board 305 and theouter housing 302, as shown in FIG. 5.

One or more data transfer terminals 532 and power transfer terminals 716are embedded at or near the surface of the probe housing 302 tofacilitate data and power transfer, respectively, between the probe 300and the MCD 800 (FIG. 8). In the present embodiment, the terminals 532,716 are ring-shaped so as to permit data/power transfer in anyrotational orientation of the probe 300 around its longitudinal axis;however, it will be recognized that other terminal shapes andconfigurations may be used.

The lens cover 308 shown in FIG. 3 is designed to protect the lenses 306a, 306 b, 306 c from becoming occluded by substances present in theintestine of the patient during probe travel. Ideally, the patient willbe restricted from eating or ingesting any substance for a suitableperiod prior to probe use so as to minimize any such occlusions;however, the lens cover 308 further assists in maintaining the lensesclear prior to use. The lens cover 308 of the present embodiment is athin membrane (on the order of a few thousandths of an inch thick) andis comprised of a substantially clear gelatin-like substance comparableto that commonly used to contain and deliver pharmaceutical products(such as so-called “gel caps” which are well known in the pharmaceuticalarts) or equivalent thereof. The design and composition of the lens gelsubstance is, in the present embodiment, controlled so as to provide atimed dissolution within the patient. For example, if it is estimatedthat the intestinal motility of the patient is X cm/hr, and the regionof the intestine desired to be inspected using the probe 300 is Y cmfrom the point of introduction of the probe, then the lens cover 308 canbe chosen to dissolve in roughly Y/X hr or less (allowing for somemargin of error). The lens cover 308 of the present embodiment is shapedto conform roughly with the outer surface of the lens(es) 306 and withthe profile of the outer housing 302 such that the cover 308 ismaintained within the housing aperture 304, and provides minimal opticaldistortion, until it dissolves. Note also that a substantially clearmaterial is chosen to permit the passage of some light through the cover308 before its dissolution, although lens covers with other opticalproperties (such as selective wavelength filtration) may be used.

It should be noted that while the present embodiment makes use of a lenscover 308, the use of such cover may not be necessary in certainapplications, and therefore need not be present. Furthermore, while thepresent embodiment describes a lens cover which is chemicallydissolvable, other types of lens covers may be employed with the presentinvention. For example, a mechanical shutter arrangement could be usedto selectively cover/uncover the lenses 306. Alternatively, a lens coverwhich dissolves or otherwise alters its properties when exposed to anelectrical current or coherent electromagnetic radiation may beemployed. A permanent (i.e., non-dissolving) lens cover having desirableoptical properties could also be used.

Referring now to FIG. 4, a front view of the smart probe 300 of FIG. 3is shown, illustrating the relationship of the housing aperture 304,lenses 306, the CCD array 402, and the lens cover 308. Specifically, theaperture 304 is sized and shaped to permit light of varying wavelengthsto impinge upon the active region 404 of the CCD array 402, and toaccommodate the optical light lens 306 b which is positioned laterallyto the main lens 306 a in this embodiment. The aforementioned lens cover308 generally conforms to the outer surface of each of the lenses 306 a,306 b, thereby acting as a protective cover for each before dissolution.As will be described in greater detail herein, the optical lens 306 bacts to transfer and distribute broad spectrum visible light generatedwithin the probe 300 to intestinal tissue in proximity to the lenses.Remitted or reflected visible is passed through the main lens 306 a(which is chosen to be effectively transparent to a broad range ofwavelengths in the spectral regions of interest) to the CCD array 402.The main lens 306 is, in the embodiment of FIGS. 3 and 4, asubstantially convex lens designed to gather and more narrowly focusenergy originating from various positions outside the probe 300 onto theCCD array 402. The optical lens 306 b is, conversely, designed toradiate and distribute light incident on its inner surfaces (via theassociated fiber optic bundle, described below) more broadly within theintestine.

The CCD array 402 of the present embodiment is a multi-pixelsemi-conductive device having anti-blooming protection, and beingsensitive to various wavelengths of electromagnetic radiation. A TexasInstruments Model TC210 192×165 pixel CCD image sensor is chosen for usein the present embodiment, based on its performance attributes, spectralresponsivity, and size (i.e., the package outline is roughly 5 mm by 3mm), although myriad other devices (CCD or otherwise) could be used withequal success. The operation of the CCD array 402 is described ingreater detail below.

Referring now to FIGS. 5 and 5 a, cross-sections of the probe 300 ofFIGS. 3 and 4 are illustrated. The probe outer housing 302 generallycontains a number of different components in its internal cavity 303including the aforementioned lenses 306 and CCD array 402, as well as alight emitting diode (LED) 504, a single mode fiber optic bundle 506,and one or more inductive data transfer terminals 532. A number ofdiscrete or integrated semiconductor components are also present withinthe probe 300, including a “flash” analog-to-digital converter ADC 512,sample and hold circuit 514, parallel and serial drivers 516, 518,microcontroller (or microprocessor) 520, clock driver 524, and a datainterface circuit 526 as described in greater detail below. The LED 504is located roughly co-linearly with the central axis of its lens 306 bwith the fiber optic bundle 508 disposed there between as shown in FIG.5. The LED 504, its fiber optic bundle 508, and its lens 306 b areoptically coupled so as to transmit light energy to the lens in anefficient manner. The A/D converter 512, drivers 516, 518,microcontroller 520, and other electronic components are disposed withinthe cavity 303 on one or more miniature printed circuit board assemblies(PCBAs) 510 in a space-efficient manner, with the semiconductorcomponents being disposed and electrically connected on either side ofthe assemblies 510. The semiconductor packages are chosen so as to fitwithin the housing, as discussed in more detail herein. One or moreinductive data transfer terminals 532 generally in the form ofcircumferential rings are disposed within the outer housing at or nearthe surface thereof as previously described in order to provide for datatransfer between the probe 300 and the remote unit 802 of the MCD dataprocessing and analysis equipment 800 external to the patient (seediscussion of FIG. 8 below). Additionally, one or more inductive powertransfer terminals 716 are positioned on the outer portion of thehousing to facilitate inductive power transfer between the MCD and theprobe 300. Inductive power transfer is chosen in the present embodimentso as to obviate the need for a chemical battery or other potentiallyhazardous power source within the probe 300, although a battery may beused. Alternatively, in another embodiment, a radio frequency (RF)oscillator and supporting circuitry (not shown) is disposed within thehousing 302 on the PCBA 510 to receive radio frequency energy generatedexternally to the patient and convert this energy to direct currentpower within the probe 300.

So as to fit within the limited volume of the cavity 303, each of theaforementioned components 504, 510, 512, 514, 516, 518, 520, 524, 526 ischosen to have the minimum physical profile. While several discretecomponent functions are depicted in the functional block diagram of theprobe data acquisition and transfer circuitry 600 (described below withreference to FIG. 6), in actuality many of these functions can beintegrated and performed by a lesser number of devices so as toeconomize on space. For example, a Texas Instruments MSP430x MSP ultralow power microcontroller (such as in the “DW package”) incorporatinginternal memory, clock, and ADC may be used in the present embodiment.Application specific integrated circuits (ASICs), FPGAs, or other customICs having a high degree of integration may also be used for suchpurposes, as described in greater detail below with respect to FIG. 16.Such integration is desirable in the present invention, and is presentlywell within the capability of those skilled in the semiconductor designand fabrication arts. Alternatively, a larger number of discretecomponents (as shown in FIG. 5) may be used. For example, a TexasInstruments TLV2543C flash ADC with a 20 pin “DB” package (roughly 8mm×7.5 mm×2 mm) may be used as the ADC 512 of the present embodiment.This package more than adequately fits within the aforementioned 12 mmouter housing 302 (assuming a 0.5 mm housing wall width), whilepreserving space for the other components. Preferably, a BGA (ball gridarray) package is utilized to eliminate leads along the edge of thepackage(s) and further economize on space. It will be appreciated,however, that a wide variety of integration schemes, packages, profiles,and lead (pin) structures may be used in the present invention in orderto simultaneously fit all of the desired components within theaforementioned outer housing 302.

The circuit board assemblies 510 of the present embodiment arepreferably multi-layer boards having a plurality of circuit traces,vias, and contact pads disposed therein to facilitate electricalinterconnection of the various terminals of the integrated circuits(ICs) and any discrete electrical components (such as the LED 504,resistors, capacitors, or transistors). The design and fabrication ofsuch circuit boards is well known in the electrical arts. Electricalinterconnection between the multiple PCBAs 510 of FIG. 5 is accomplishedvia miniature flexible electrical tracing (not shown). Note that in thepresent embodiment, the PCBAs 510 are disposed in a generallylongitudinal fashion (i.e., parallel to the longitudinal axis of theprobe housing 302); however, other orientations, such as transverse tothe longitudinal axis, could be used.

The LED 504 used in the embodiment of FIGS. 3-5 is a standard, lowvoltage light-emitting diode having a spectral emission characteristiccentered in the visible wavelengths. In the present embodiment, a “whitelight” LED of the type well known in the electrical arts is preferred,although other types, power ratings, and spectral outputs are possible.This LED 504 is used as an optical illumination source for the CCD array402 previously described. Specifically, light generated by the LED ispassed via its fiber optic bundle 508 to the optical lens 306 c andradiated out of the probe 300 into the region immediately surroundingthe CCD array 402. The fiber optic bundle is, in this embodiment, asingle mode optical fiber of the type well known in the opticaltransmission arts. Light reflected by the interior surfaces of thepatient's intestine is gathered by the main lens 306 a and focused onthe CCD array 402, including the visual sub-array 402 b, where itgenerates charge within the individual CCD array cells. The voltage andpower rating of the LED 504 is chosen to be compatible with the desiredlight intensity, power supply circuit capacity, and system voltageavailable within the probe. In the present embodiment, a milliwatt LEDis used having a voltage rating on the order of 2-5 Vdc, although othermay be used.

Referring now to FIG. 6, one embodiment of the data acquisition,processing, and transfer circuit 600 of the smart probe of FIGS. 3-5 isdisclosed. As previously described, the circuit 600 of the presentembodiment comprises a number of components including, inter alia, a CCDarray 402, parallel and serial drivers 516, 518, sample and hold circuit(SHC) 514, system clock 524, microcontroller 520, amplifier 522, ADC512, and data transfer sub-circuit 526. Other electronic elements (suchas capacitors, resistors, transistors, and diodes; not shown) are alsoused to facilitate operation of the circuit 600; the use of suchcomponents is well known in the relevant arts and accordingly will notbe discussed further herein. Furthermore, it will be noted that suchelectronic elements are ideally integrated with one or more of theaforementioned components 512, 514, 516, 518, 520, 522, 524, 526 inorder to minimize space consumed within the probe outer housing 302.

As shown in FIG. 6, the CCD array is driven by the parallel and serialdrivers 516, 518 based on a user-defined clock signal output from theclock/timer 524 and controlled by the microcontroller 520. Analogsignals output from the CCD array are amplified by amplifier 522 andpassed to SHC 514. Analog signals output from the SHC 514 are rapidlyconverted by the ADC 512 into digital signals, the latter being input tothe data transfer sub-circuit 526. A “flash” ADC (i.e., one with asampling rate on the order of microseconds or less) is used to permitstreaming of video data at video rates, typically 7-20 MHz. A 10 or12-bit resolution ADC may be used, for example, to accommodate thedynamic range of the CCD. The required ADC resolution can generally bedetermined by the following relationship:N≧(DR/6.02)

Where:

N=Number of data bits

DR=Dynamic Range of CCD in db

The data transfer sub-circuit 526 comprises a modulator 528,demodulator/filter 529, transistor stage 530, and data transfer terminal532. The construction and operation of such inductive data terminals iswell known in the electronic arts, and is described in, inter alia, U.S.Pat. No. 4,692,604 “Flexible Inductor” issued Sep. 8, 1987, which isincorporated herein by reference in its entirety. Note that in thepresent embodiment, the “flexible” inductor of the '604 patent isconfigured so as to form a circumferential ring within the probe outerhousing, as shown in FIG. 3. A high frequency (MHz) clock signal issupplied by the clock 524 to the modulator 528 so as to generate an accarrier. The data signal output from the ADC 512 is used by themodulator 528 to modulate the aforementioned ac carrier, therebyproducing an amplitude modulated ac waveform on the coil of the dataterminal 532 by way of the transistor stage 530. The output of the probedata terminal 532 is a magnetic flux which varies according to theamplitude modulated ac signal carried on the terminal coil. The coil 542of the MCD remote unit data terminal 540 is inductively coupled to theprobe data terminal coil via the magnetic flux; accordingly, anamplitude modulated, alternating current signal of the same phase andfrequency is generated in the remote unit coil 542. This signal is thendemodulated using, for example, a diode and filter capacitor asdescribed in U.S. Pat. No. 4,605,844, “Computerized Transaction CardWith Inductive Data Transfer”, issued Aug. 12, 1986, which is alsoincorporated by reference herein in its entirety. The resultingdemodulated data signal, a replica of the data signal supplied by theoutput of the ADC 512, is input to the front-end processing (e.g., DACor DSP) of the MCD, as described with reference to FIGS. 8 and 9 below.It will be further recognized that the design of the data transfersub-circuit 526 must consider the video data rates previously described(typically 7-20 MHz).

The demodulator/filter 529 performs two functions: (i) demodulating thecontrol and data signals sent by the MCD microprocessor during probestartup and operation; and (ii) isolation and filtering of any errantpower transfer signal which couples to the inductive coil(s) of the datatransfer terminal 532.

Referring now to FIG. 7, one embodiment of the inductive power transfercircuit 700 used in the smart probe of FIGS. 3-6 and MCD remote unit 802is described. Similar to the inductive data transfer sub-circuit 526illustrated in FIG. 6, the power transfer circuit 700 utilizes aclocking signal generated by the clock 702 in the MCD remote unit 802 tosupply a parallel transistor stage 703 including two pairs oftransistors 704 a, 704 b and associated MOSFETs 706 a, 706 b. One pairof transistors 704 a is supplied via an signal inverter 708 so as toinvert the phase (i.e., shift by 180 degrees) of the signal with respectto the non-inverted signal supplied to transistors 704 b. An alternatingcurrent waveform (of a different frequency than that imposed upon thedata transfer terminal(s) 532) is accordingly generated within the coil710 of power transfer terminal 712, which is inductively coupled to thecoil 714 of the power transfer terminal(s) 716 in the probe 300. A diode(rectifier) stage 720 including filter capacitor (not shown) is used toconvert the induced ac signal in the probe coil 714 to direct current. Avoltage regulator and conversion circuit 722 is used to regulate andadjust the voltage of the converted dc power prior to supply to theother components 402, 504, 512, 514, 516, 518, 520, 522, 524, and 526within the probe 300 via the various voltage busses 730, 732, 734. Theconstruction and operation of voltage regulating and conversion circuitsis well known in the electrical arts, and will not be discussed furtherherein. U.S. Pat. No. 4,605,844, previously cited herein, describes theconstruction and operation of inductive power transfer circuits such asthat utilized herein in greater detail.

Similarly, it will be noted that the method of clocking signal recoverydescribed in the above-referenced patent may be utilized in the presentinvention to obviate the clock 524 of FIG. 6. Specifically, the acwaveform transferred from the MCD remote unit 802 can be used togenerate a clock signal prior to rectification by the diode stage 720using a clock recovery circuit 740. This clock signal may then be usedto drive those components requiring a clock signal, such as the CCDarray 402, ADC 512, etc.

It will be further recognized that while the present embodiment utilizesinductive data and power transfer, other methods of such transfer arepossible. See, for example, the capacitive data transfer apparatusdescribed in U.S. Pat. No. 4,816,654, “Improved Security System for aPortable Data Carrier”, issued Mar. 28, 1989, which is incorporatedherein by reference in its entirety.

Referring now to FIG. 8, the monitoring and control device (MCD) 800 ofthe present invention includes, in a first embodiment, a remote unit 802which can be placed in close proximity to the patient's abdomen in theregion of the intestine where the probe 300 is located to permitinductive data and power coupling thereto. The remote unit 802 includes,inter alia, one or more inductive data terminals 540, and one or moreinductive power transfer terminals 712 These terminals 540, 712 arelocated within the unit so as to provide adequate separation duringoperation, yet still permit simultaneous contact with the probe 300while in the patient. The operation of these terminals is described ingreater detail above with respect to FIGS. 6 and 7. As shown in FIG. 8,a circular “ring” configuration is used for the terminals 540, 712 inthe present embodiment so as to minimize the effects of differentazimuthal orientations of the remote unit 802 with respect to the probe300, although it will be appreciated that other configurations (such aspins, rods, strips, etc. may conceivably be used). As the probe 300slowly moves within the intestine, the remote unit 802 is movedaccordingly by the operator so as to maintain contact therewith. Sincethe inductive coupling between the data and power transfer terminals540, 712 of the remote unit and terminals 532, 716 of the probe issubstantially affected by the distance between the respective terminals,as well as the interposed material (tissue, fluids, etc.), the remoteunit 802 must be periodically moved while the probe 300 is in use.

The remote unit is connected to the MCD main unit 804 via a standarddata transmission cable 806 of the type well known in the electricalarts. As further illustrated in FIG. 9, the MCD main unit 804 of thepresent embodiment includes, inter alia, a “flash” digital to analogconverter (DAC) 902, digital signal processor (DSP) 904, microprocessor906, encoder 908, video display driver 910, display unit 912, videomemory 914, and non-volatile storage device 916. Image data transmittedfrom the probe 300 is passed to the main unit 804 from the remote unit802, de-compressed if required by the DSP 904, converted to an analogformat by the DAC 902, coded by the video encoder 908, and displayed onthe display unit 912. These displayed visual or autofluorescence imagesconstitute one form of diagnostic aid according to the presentinvention, although it will be recognized that other such aids (such asultrasound images) may be produced. Images may be stored in the storagedevice 916 for a variety of functions (such as later retrieval orenhancement) if desired, as is well known in the electronic arts. Themicroprocessor 906 acts to control the operation of the MCD 804 as wellas the probe 300 via data signals transmitted to the probe duringstartup and operation. Specifically, the microprocessor 906 of the MCDgenerates and passes control data to the microcontroller 520 of theprobe via a modulator circuit 911 and the inductive data terminals 532,540 on startup to initiate microcontroller control of the probe. Theprobe microcontroller 520, which is connected to and receives input fromthe clock 524 (or alternatively, the clock recovery circuit 740associated with the power transfer circuitry), switches power to theremaining (non-powered) probe components such as the SHC 514 and ADC 512and generates the necessary signals to the various probe components(based on its internal programming) so as to initiate operation of theLED 504, collection of image data via the CCD array 402, and subsequentprocessing/transfer of the collected data.

The remote unit 802 of the MCD 800 is, in a second embodiment, a bandwhich is fitted around the abdomen of the patient (not shown). This bandincludes a plurality of individual data and power transfer terminalseach of which are capable of transferring data and power inductivelybetween the MCD and the probe 300. The terminals are physically arrangedin an interleaved fashion (alternating data and power transferterminals) so as to provide a high density of terminals yet minimize anyinterference between terminals. The data terminals are electricallyarranged so as to allow the MCD to select and display data received fromone or more of the data terminals (channels). This multi-terminalapproach is used to allow the probe to maintain contact with the MCDremote unit with minimal or no movement of the remote unit. As thecoupling between one set of data terminals is increased with respect tothe other terminals, the signal quality for that channel increasesaccordingly. In one embodiment, the digital data received from the dataterminals is input to a high frequency multiplexer. The multiplexergenerates a single multiplexed output (based on the multiple datachannel inputs) which is input to a DSP. The DSP samples and analyzesthe data on the single multiplexed channel for each input channel usingan internal algorithm to evaluate the strength and quality of signal onthat input channel. The microprocessor selects the most viable channelsat any given time based on the output of the signal sampling algorithmrunning on the DSP, and utilizes the selected input channel as the datasource for the DAC and video driver.

Conversely, all of the multiple power transfer terminals in the remoteunit of the second embodiment are driven synchronously andsimultaneously by the MCD so as to permit inductive coupling with theprobe at all times, thereby minimizing power “drop outs”.

FIG. 10 a is a perspective view of a second embodiment of the smartprobe of the present invention. The probe 1000 of FIG. 10 a comprises anouter housing 1002 having a generally cylindrical shape with roundedends (“capsule”), an inner cavity 1003 (not shown), and a lens aperture1004 positioned in one end of the housing 1002. Three lenses 1006 a,1006 b, 1006 c are mounted in alignment with the aperture 1004, andoptionally protected by a lens cover. The third lens 1006 c of thepresent embodiment is used to distribute laser (coherent) light energygenerated by a laser diode which is described in greater detail below.The CCD array 1010 includes two sub-arrays 1010 a, 1010 b (FIG. 10 b)for the collection of visible ambient and light emitted byautofluorescence, respectively. The probe 1000 further includes adigital signal processor (DSP) and memory (not shown) which facilitateprocessing and storage of the data collected by the CCD sensor andcontrol of the probe, as described below. Data transfer terminals 1040and power transfer terminals 1043 are embedded at or near the surface ofthe housing 1002, as in previous embodiments.

Referring now to FIG. 10 b, a front view of the smart probe 1000 of FIG.10 a is shown, illustrating the relationship of the housing aperture1004, lenses 1006, the CCD array 1010, and the lens cover 1008.Specifically, the aperture 1004 is sized and shaped to accommodate theCCD array 1010 and associated main lens 1006 a, laser energy lens 1006b, and the optical light lens 1006 c. The laser and optical lenses 1006b, 1006 c are positioned laterally to the main lens 1006 a in thisembodiment. The aforementioned optional lens cover 1008 conforms to theouter surface of each of the lenses 1006 a, 1006 b, 1006 c. Bothremitted visible light and emissions resulting from the autofluorescenceof the surrounding tissue are passed through the main lens 1006 a (whichis chosen to be effectively transparent to a broad range of wavelengthsin the spectral regions of interest) to the CCD array 1010. The mainlens 1006 a is, in the embodiment of FIGS. 10 a and 10 b, asubstantially convex lens designed to gather and more narrowly focusenergy originating from various positions outside the probe 1000 ontothe CCD array 1010. The laser lens 1006 b and optical lens 1006 c are,conversely, designed to radiate and distribute light incident on theirinner surfaces (via their associated fiber optic bundles) more broadlywithin the intestine.

The CCD array 1010 of the present utilizes an interleaved design wherebyindividual charge collecting cells having sensitivity to broad spectrumvisible light are spatially mixed with cells having sensitivity within arange of wavelengths ideally centered on the autofluorescence peakassociated with biological tissue within the interior of the patient'sintestine (530 nm in the present embodiment). Hence, two separate CCDsub-arrays are formed (each having approximately half of the totalnumber of cells in the array 1010); (i) a “visible” light sub-array 1010a, and (ii) an “autofluorescence” sub-array 1010 b. As shown in FIG. 10b, the pixels of the two sub-arrays 1010 a, 1010 b are physicallyinterleaved such that alternation between the pixels of each sub-arrayoccurs in the row dimension only. Therefore, when reading voltage dataout of the array 1010 on a row-by-row basis, data from successive cellswill be associated with alternating sub-arrays. When data is seriallyread out of the array 1010 of FIG. 10 b in the column direction, anentire column is associated with the same sub-array. This arrangement isused to permit the data acquisition circuitry (described further belowwith respect to FIG. 12) to readily parse data from the two sub-arrays1010 a, 1010 b and store it at different locations within the devicememory 1026. It will be recognized that other types of interleaving ofthe array 1010 may be used in conjunction with the present invention,however. For example, alternation of pixels on a column basis may beused. Alternatively, pixels could be alternated on both a row and columnbasis. Furthermore, interleaving of the pixels need not be used; rather,a single multifunction CCD array, or a system of two or more discreteCCD arrays arranged in some other spatial relationship (such asside-by-side, or over-under) could be used, either with a single lens1006 a as shown in FIG. 10 b, or separate, dedicated lenses.

Referring now to FIG. 11, a cross-section of the probe 1000 of FIGS. 10a and 10 b is illustrated. The probe outer housing 1002 generallycontains a number of different components in its internal cavity 1003including the aforementioned lenses 1006 a, 1006 b, 1006 c and CCD array1010, as well as a semiconductor laser 1012, light emitting diode (LED)1014, two respective single mode fiber optic bundles 1016, 1018, and oneor more data transfer terminals 1020. A number of discrete or integratedsemiconductor components are also present within the probe 1000,including, inter alia, an analog-to-digital converter (ADC) 1022, adigital processor 1024, microcontroller 1025, digital memory 1026 withintegral memory controller, as described in greater detail below. Thesemiconductor laser 1012 and LED 1014 are located approximatelyco-linearly with the central axis of their respective lenses 1006 b,1006 c, with the fiber optic bundles 1016, 1018 disposed there betweenas shown in FIG. 11. The laser and LED 1012, 1014, their respectivebundles 1016, 1018, and respective lenses 1006 b, 1006 c are opticallycoupled so as to transmit light energy to the lenses in an efficientmanner. The ADC 1022, signal processor 1024, memory 1026, and otherelectronic components are disposed within the cavity 1003 on one or moreminiature printed circuit board assemblies (PCBAs) 1030 in aspace-efficient manner, with the semiconductor components being disposedand electrically connected on either side of the assemblies 1030. One ormore data transfer terminals 1040 in the form of circumferential ringsare located within the outer housing at or near the surface thereof inorder to provide for data transfer between the probe 1000 and the MCDremote unit (not shown). Additionally, a power transfer circuit 1042with transfer terminals 1043 similar to that described with respect tothe embodiment of FIGS. 3-7 is disposed within the housing 1002 on aPCBA 1030 to receive and demodulate inductive modulated energy generatedexternally to the patient by the MCD remote unit. Optionally, in yetanother embodiment, a NiMH or comparable miniature battery (not shown)and supporting circuitry may be included within the outer housing 1002as a power source in lieu of the aforementioned inductive power circuit1042.

As previously discussed with respect to the embodiment of FIGS. 3-7, thepackage profiles of the components used within the present embodimentare chosen so as to permit all of the above-described components to befit within the outer housing. This becomes particularly critical withrespect to the embodiment of FIGS. 10 a, 10 b, and 11, since there aresubstantially more components contained within the outer housing 802.The size of each component package must be weighed against the necessityof the component and the overall available space within the probehousing 1002. For example, when choosing a DSP package, the necessaryMIPS, degree of integration of other functions within the DSP (such as,DMA, internal memory, etc.) are balanced with the available space withinthe housing. Similarly, the memory storage capacity is balanced with thephysical package size in order to optimize all parameters. Also, aspreviously discussed, the use of highly integrated multifunction devicessuch as that of FIG. 16 is desirable in order to reduce the size of theprobe 1000. For example, embedded memory (i.e., that integrated withinthe DSP or other component package) may be employed as the capability ofsuch devices increases. Furthermore, the placement of the individualcomponents at various locations on the PCBAs 1030 (as well as theplacement of the PCBAs themselves) is optimized for space.

In light of the foregoing, it will be appreciated that the size andshape of the probe outer housing 1002 can be adjusted to accommodateinternal components of varying sizes, consistent with the requirementthat the housing be sized and shaped to permit passage through thedesired portion of the patient's intestinal tract. Typically, theileocecal valve at the juncture of the small and large intestines willconstrain the maximum diameter of the probe housing. The probe housing1002 of the embodiment of FIGS. 10-11 is larger (roughly 40 mm inlength, and 15 mm in diameter) than that of the embodiment of FIGS. 3-5(roughly 30 mm in length, and 12 mm in diameter), although it will berecognized that other sizes and shapes may be used.

The laser 1012 of the smart probe 1000 is now described. A semiconductor(diode) laser is used in the embodiment of FIGS. 10-11 to generate laserenergy in the desired wavelength band. In the present embodiment, acenter wavelength of 530 nm (corresponding to green light) is used,although it will be recognized that other wavelengths may be chosenbased on the response of certain types of tissue and the needs of aspecific application. As shown in FIG. 2, the ratio of measuredfluorescent intensity for diseased tissue to that of normal tissue isminimized (and both the absolute intensity and intensity differencemaximized) at roughly 530 nm, thereby effectively increasing theresolution and signal-to-noise ratio of the system without additionalprocessing. A micro-package diode laser is utilized based onavailability and cost, output power, size, and power consumptionconsiderations, although other lasers may be used. A laser drivercircuit 1013 (such as a model NS102 manufactured by NVG Corporation) isused in conjunction with the aforementioned laser diode in order tocontrol the operation and output of the diode. Note that the size of thelaser diode and driver circuit (on the order of a few millimeters in alldimensions) allows conservation of space within the probe outer housing1002. The laser 1012 may be configured to operate in either pulsed or CW(continuous wave) modes, or both, depending on the needs of theoperator. Switching between modes of operation is accomplished via themicrocontroller 1025, as is well known in the art.

In yet another embodiment, the aforementioned laser diode 1012 andassociated circuitry and power supply are adapted to ablate intestinaltissue through direct irradiation with coherent electromagnetic energy.Due to the increased power output requirements of ablation, the laserdiode is adapted to radiate increased power as compared to theautofluorescence laser diode previously described herein. Thesemiconductor laser of the present may generate for example, between0.05 W and 1.0 W of continuous wave (cw) laser power at a wavelength ofbetween 800 nm and 900 nm, although other wavelengths may besubstituted. The laser may consist of a single semiconductor laserelement, an array of semiconductor lasers, several individualsemiconductor lasers or a combination thereof. The coherent light energygenerated by the semiconductor laser(s) is transmitted into the singlemode optical fiber (bundle). The fiber may contain a single fiber orseveral optical fibers to accommodate the increased light intensity. Inthe preferred embodiment, a single laser diode generating 0.15 W cw of800 nm laser energy out of a 150 micron diameter, 0.25 NumericalAperture (NA) optical fiber, although other configurations may be used.

An exemplary semiconductor laser diode 1012 comprises a GaAs substrateupon which an N-doped AlGaAs cladding layer is deposited, as is wellknown in the semiconductor arts. Upon this structure, a single quantumwell of GaAs is formed as a thin layer between the layers of AlGaAs, theindex of infraction varying as the layer proceeds from the claddinglayer to the quantum well. A semiconductor laser diode, as the onepreviously described, will produce an output in the portion of thequantum well region when a sufficient voltage difference is maintainedbetween the N- and P contact layers. Other types of devices may also besubstituted, consistent with the space and electrical power constraintsof the particular probe configuration with which the laser diode isused.

Note that the supply of such power (i.e., 0.15 W=0.15 J/s) for thesemiconductor diode ablation laser is derived either from on-probesources; e.g., battery, structural capacitor (described below), orinductive/RF power coupling (previously described), and/or through useof a “trailer” probe as described subsequently herein with respect toFIG. 34. As will be readily appreciated, the trailer probe may be usedto store additional energy for use by the laser in vivo, including forexample additional battery cells or structural capacitance.

Referring now to FIG. 12, one embodiment of the data acquisition,storage, and transfer circuit 1200 of the present invention isdescribed. As shown in FIG. 12, the circuit 1200 comprises generally acombined CCD array 1010, analog-to-digital converter (ADC) 1022, digitalsignal processor (DSP) 1029, microcontroller 1025, random access memory(RAM) with integral memory controller 1026, and a data transfersub-circuit 1027. Other components include a system clock/timer 1044,parallel/serial drivers 1046, 1048, sample and hold circuit 1050, datacompression algorithm (running on the DSP), and data transferterminal(s) 1040. The function and operation of these components aredescribed in greater detail below.

As previously described, the CCD array 1010 or other device is used togather light energy of varying wavelengths, and produces a voltageoutput which is proportional to the intensity of the incident light.Note that during laser operation, the cells of the CCD may be drained ifrequired to prevent damage. The analog output of the CCD array is fed tothe ADC 1022, which converts the analog signal to a digitalrepresentation. The ADC of the present embodiment has at least twoanalog input channels which are multiplexed to permit the conversion ofanalog voltage data generated by either of the CCD sub-arrays 1010 a,1010 b to a digital format. The digital output of the ADC is fed to theDSP 1024 which performs a variety of control and signal processingfunctions including demultiplexing of the multiplexed ADC signals, andsignal compression for storage in the memory 1026. The DSP takes thedigital data received from the ADC, demultiplexes and formats it, andoptionally compresses it for storage within the memory using any numberof data compression techniques such as pulse code modulation (PCM) ordelta pulse code modulation (DPCM), which are well known in the signalprocessing arts. Data compression is performed within the DSP using analgorithm adapted for such purpose which is stored within the program orflash memory of the DSP 1024 or, alternatively, within the off-chipmemory 1026. It will be appreciated that while a DSP having a programmemory is used in the present application, other types of processors maybe substituted based on the chosen data acquisition and transferproperties. A discretely packaged DSP such as a Texas InstrumentsTMS320C2xx series processor (roughly 14 mm×14 mm×2 mm in the “PN” PQFPpackage) can be used in the present embodiment, although as previouslydiscussed, it is desirable to integrate as many probe functions into oneIC as possible in order to economize on space within the probe outerhousing. Note that if data compression is not used, the need for a DSPis obviated, since other functions may be performed by themicrocontroller 1025. The DSP 1024 interfaces with the memory controllerwithin the memory 1026 which controls the accessing and storage of datatherein. The probe memory 1026 of the present embodiment is a standard3.3.V logic static random access memory (SRAM), although other types ofmemory (such as DRAM, SDRAM, double-data rate (DDR) SDRAM, “flash”, orSLDRAM) may be used. 3.3.V SRAM is preferred based on its comparativelylow power consumption and static data storage properties. The memory1026 is chosen to have adequate storage capacity for compressed (ornon-compressed) data output from the DSP 1024 during imaging. The memory1026, depending on the operating mode of the probe (e.g., streaming dataexternally via the data transfer sub-circuit, or storing internally),must be able to store a sufficient amount of data so as to permit (i)any buffering of the data necessitated by the data transfer sub-circuit1026, and (ii) storage of at least one frame (and preferably more)obtained by the CCD array 1010. In the present embodiment, a sub-arrayof 31,680 pixels is used (192 pixels per line, 165 lines per sub-array);hence, a memory storage capacity corresponding to binary representationsof at least this number of pixels is used. The memory storage capacityneeded is further determined by the type and efficiency of compressionutilized, if any. Compression is used not only to minimize the size andincrease the capacity of the memory 1026 within the probe, but also tominimize the bandwidth necessary to transmit data via the data interfacesub-circuit 1027.

It will be recognized that while the foregoing descriptions of the smartprobe of the present invention are cast in terms of embodiments havinglaser and/or broad spectrum visual light sources, a CCD array, inductivepower and data transfer, and signal processing and/or data storagecapability, any number of different combinations of these features (oreven other features) may be used consistent with the present invention.For example, a probe having a laser diode, CCD array, capacitive datatransfer, and battery power supply is contemplated. Alternatively, otherembodiments of the smart probe could include a device for obtaining amicrosample (biopsy) of intestinal tissue, or for delivering a dose of adrug, chemical, or even ionizing radiation to, inter alia, otherwiseinaccessible portions of the intestine of the patient. A large number ofalternate configurations are possible, all being within the scope of thepresent invention. Some of these alternate configurations are describedin greater detail herein with respect to FIGS. 16-35 c.

Endoscopic Delivery Device

Referring now to FIG. 13 a, a first embodiment of the endoscopicdelivery device of the present invention is disclosed. Specifically, thedevice 1300 of FIG. 13 a includes a housing 1302 located at its distalend 1304, the housing having an internal cavity 1306 sized to receivethe smart probe 300 of FIG. 3 (or alternatively, other embodiments). Thehousing 1302 and distal end of the device 1304 are sized so as to permitpassage through the esophagus and stomach of a patient. The cavity 1306is open at the distal end of the device, such that the smart probe 300may be inserted into the cavity via an aperture 1308. A closure ordiaphragm 1310 is mounted over the aperture 1308 as shown in FIG. 13 a.The closure 1310 is, in the present embodiment, a substantiallyhemispherical membrane which is scored or perforated in one or moreareas of its surface so as to be substantially weakened in these areas(see FIG. 13 b). In one embodiment, the closure is scored radically asshown in FIG. 13. One or more tubes 1316 running down the length of thedelivery device 1300 terminate in the cavity 1306 in the region 1312behind the probe 300 (when inserted in the housing 1302). A pliable,ring-shaped seal 1314 is fitted to the interior of the housing near theaperture 1308, the seal having an inner diameter of its sealing surfaceapproximating that of the probe outer housing 302. The seal 1314 issized so as to permit easy movement of the probe 300 through the seal,yet also maintain adequate sealing against the gross leakage of fluid(or gas) past the seal. A non-toxic fluid or gas (such as water, or air)is applied via the tube(s) 1316 during implantation of the smart probein order to expel the probe from the housing 1302 and cavity 1306.Collectively, this arrangement comprises the release mechanism.

As the portion of the cavity 1306 behind the probe and seal 1314 ispressurized by the fluid/gas, the probe 300 is displaced forward withinthe cavity so as to contact the closure 1310. The scores 1320 in theclosure 1310 will eventually yield under the force exerted by the probe,thereby rupturing the closure and allowing the expulsion of the probefrom the cavity. It will be recognized that the yield stress of theclosure scores 1320 is preferably set such that an extremely lowfluid/gas pressure is required to rupture the closure, thereby causingthe probe 300 to move slowly out of the housing 1302 and preventing anypotential trauma to the interior region of the patient's intestine fromthe expulsion transient. Additionally, the rate of pressure increasewithin the cavity 1306 can readily be controlled by the operator usingany number of available means such as a hand pump, low volumetric flowrate mechanical pump, or the like.

While the present embodiment describes a mechanically ruptured closureand associated fluid system for expelling the probe, it can beappreciated that a number of different ways of rupturing or dissolvingthe closure may be employed. For example, minute electrical filamentscould be used to melt portions of the closure prior to probe expulsion.Alternatively, the closure could be dissolved or weakened by thepresence of one or more chemical agents, or even light energy. It willbe further recognized that the closure is optional and may not even beused in certain applications, especially if a lens cover 308 is used onthe probe 300.

In the embodiment of FIG. 13 a, a narrow fiber optic bundle 1322 andlens 1323 is routed around the periphery of the probe and within thehousing 1302 of the endoscopic delivery device 1300 in order to assistthe operator in locating and implanting the smart probe 300. Lightgathered by the bundle 1322 and lens 1323 is transmitted to a videodisplay unit or other means of viewing (not shown). It will berecognized, however, that other means of viewing the probe 300 duringdelivery (both direct and indirect) may be used. For example, theprobe/delivery device location could be viewed using ultrasonic,magnetic resonance, or X-ray imaging.

A second embodiment of the improved endoscopic delivery device accordingto the present invention is shown in FIG. 14. In this embodiment 1401,the smart probe is biased by a spring or other means (such as an elasticmember) toward the aperture 1408 in the housing such that the probe isurge from the cavity 1406 and housing 1402, as shown in FIG. 13 b. Aretaining detent or latch 1440 is positioned at or near the aperture1408 and engages a recess 1442 in the outer housing 302 of the probe 300such that when the probe is inserted into the cavity and latched, thespring 1446 (or other biasing means) biases the probe 300 against thelatch 1440. The latch is, in the present embodiment, actuated by aminiature cord or cable 1450 disposed within a channel 1452 runninglongitudinally up the side of the delivery device 1401, although it willbe recognized that a myriad of different release mechanisms may be used.Alternatively, an outer closure (not shown) may be used in place of thelatch 1440 to retain the probe 300 within the housing against thebiasing force until the closure is sufficiently weakened by electricalenergy, light energy, or the presence of a chemical agent.

Method of Providing Diagnosis and Treatment

Referring now to FIG. 15, a method of providing diagnosis and treatmentof a patient using the apparatus of the present invention is disclosed.

It will be recognized that while the following method recites a seriesof steps in a given order, this order may be permuted where appropriatesuch that the steps recited herein may be performed in alternatesequences. Additionally, certain steps (including, for example, theinstallation of the lens cover) may be completely omitted, or othersteps added. The following description is meant only to be illustrativeof the method of the present invention.

It will be further recognized that while not recited as a specific stepin the embodiment of the method described below, patient intestinalpreparation prior to introduction of the smart probe is essential to theproper operation of the probe while in the patient. Such intestinalpreparations exist in a myriad of different varieties and are wellunderstood by those of ordinary skill in the medical arts, andaccordingly shall not be discussed further herein.

Additionally, while the following description of the method of thepresent invention is cast in terms of delivery via an endoscopicdelivery device, it will be appreciated that other methods or forms ofdelivery device may be used, and that the method is not limited to oneform of delivery. For example, the probe may be sized such that it canbe swallowed by the patient. Ultimately, as the probe is passed throughthe stomach into the small intestine after swallowing, it will beoriented based on its shape (substantially ellipsoid or cylindrical inthe preferred embodiments) so as to facilitate data gathering.

In the first step 1502 of the instant method 1500, thetype/configuration of probe to be used is determined based on theparameters of the patient and the information desired, and a testingprotocol selected. For example, if only a visual inspection of a portionof the intestinal wall of a patient is desired, then a probe of the typedescribed with reference to FIGS. 3-7 above is selected. Such a probecan arguably have a smaller profile (due to its simpler construction ascompared to the probe of FIGS. 10-11), and therefore may be bettersuited in applications where intestinal strictures may exist.

The probe is then tested outside of the patient to verify properoperation in step 1504. Such testing may include, inter alia, testing ofthe operability of the CCD array, laser diode and DSP (if so equipped),LED, data transfer circuit, and inductive power circuit. It will berecognized that a number of different test protocols may be useddepending on, inter alia, the specific configuration of the probe.

Next, the proper lens cover is chosen for use with the probe andinstalled if desired in step 1506. As previously discussed, the lens capis in one embodiment comprised of a material which dissolves in thepresence of one or more gastric substances (or due to other conditionssuch as exposure to coherent light energy). Information regarding themotility of the patient's intestinal tract, and the location of theregion of prospective examination/treatment, may also be used in makingthe selection of the proper lens cover if appropriate. In the embodimentof FIGS. 3-5, the lens cap may simply be installed to fit within therecess around the lens 306, as described above.

In step 1508, the patient is optionally sedated using any number oftechniques which allow the probe to be inserted (via the aforementionedendoscopic delivery device) into the esophagus of the patient. Sedationtechniques are commonly used in endoscopic examination and are wellknown in the medical arts, and accordingly are not described furtherherein.

Next, in step 1510, the smart probe 300 is introduced into the patient.In one embodiment of the present method, the probe is inserted using thespecially adapted fiber optic endoscopic delivery device previouslydescribed. It will be recognized, however, that other methods ofdelivering and placing the probe can feasibly be used with equalsuccess.

In the next step 1512 of the present method, the smart probe is testedin-situ while still retained within the housing of the delivery device1300 to ensure proper data and/or power transfer between the externalmonitoring and control device (MCD) 800 and the probe. The probe 300 isfirst powered up using the inductive (or RF) signal applied from the MCDremote unit 802 via the power transfer circuit 700. Then, the CCD andprobe circuitry and LED circuitry is activated to generate ambient lightand an image using the CCD array 402. This image data is thentransferred to the MCD via the data transfer circuit 600 to verifyproper operation of the CCD and associated components. Optionally, thefunctionality of the laser 1012, 1013 and the autofluorescence CCDsub-array 402 b (if so equipped) can be verified as well. Note that ifthe lens cover 308 is utilized, the image transferred will be blurry andout of focus due to the optical characteristics of the lens cover.However, the operation of the CCD and laser can be suitably verifiedeven with the lens cover in place.

After proper operation of the probe 300 is verified, the probe ispositioned and implanted within the patient in step 1514. Ideally, theprobe 300 is implanted in the ileum region of the patient's smallintestine; however, other locations may be used. Implantation preferablyoccurs using the aforementioned fluid/gas pressurization technique whichexpels the smart probe 300 from the endoscopic device housing 1302.

Next, the endoscopic delivery device 1300 is retracted from the patientin step 1516. The smart probe 300 is then activated and tracked (or,alternatively, tracked and subsequently activated when the desired probeposition is achieved, or maintained in an activated state continuously)in step 1518. Tracking can occur in a number of ways including, interalia, via direct feedback (i.e., by maintaining continuous data transferbetween the probe and the MCD remote unit), or by using an ultrasoundimaging system.

Next, in step 1520, visual or autofluorescence image data is streamedout of the probe and/or stored, based on memory limitations, within thememory of the probe if so equipped. Note that if a lens cover 308 isutilized on the probe 300, the lens cover must be dissolved prioracquiring image data. Furthermore, if a probe having the aforementionedlaser module 1012, 1013 is used, and laser-excited autofluorescence datais desired, the laser diode will need to be activated for a period oftime beginning prior to the acquisition of autofluorescence image databy the autofluorescence sub-array 402 b.

In step 1520, data streamed from the probe 300 is processed and analyzedin the MCD 800. Note that this step may be performed at a later time;i.e., the image data can be stored within the storage device 916 of theMCD or other external storage device for later analysis.

When all data acquisition is complete, the probe is deactivated (such asby simply by powering it down) in step 1522. Lastly, in step 1524, theprobe 300 is retrieved from the patient via normal excretory function.Any remaining data stored in memory 1026 at that point may be retrievedusing the MCD 800 and data transfer circuit 600 previously described,and subsequently analyzed.

Referring now to FIGS. 16 and 16 a, another embodiment of the endoscopicapparatus of the invention is described. As illustrated in FIG. 16, theprobe 1600 includes a fully integrated low-voltage “system on a chip”(SoC) application specific integrated circuit (ASIC) 1602 of the typegenerally known in the semiconductor fabrication arts. The SoC ASIC 1602(FIG. 16 a) incorporates, inter alia, a digital processor core 1604,embedded program and data random access memories 1606, 1608, radiofrequency (RF) transceiver circuitry 1610, modulator 1612,analog-to-digital converter (ADC) 1614, and analog interface circuitry1616. The digital processor core of the illustrated embodiment comprisesan extensible reduced instruction set computer (RISC) which isadvantageously selected to be user-configurable with respect to one ormore sets of predetermined extension instructions. It will berecognized, however, that a variety of core architectures and featuresmay be used, however, depending on the particular purpose, includingHarvard architecture (separate program and data busses), very longinstruction word (VLIW), multiple multiply-accumulate stages (e.g., dualMAC), etc.

The set(s) of instructions of the RISC core of the embodiment of FIG. 16a is/are specifically adapted to efficiently perform various processingcomputations (such as multiply-accumulate (MAC) operations) and tasksassociated with the different various embodiments of the probe describedherein. For example, with respect to (visual) or autofluorescense imageprocessing, the operation and speed of filtering and/or compressionalgorithms of the type well known in the art may be enhanced through useof an optimized instruction set specifically adapted to thosealgorithms. Similarly, ultrasonic signal processing may be enhancedthrough selection of an instruction set adapted to perform, inter alia,fast Fourier transforms (FFTs) and associated “butterfly” calculations,time frequency distribution calculations (e.g., spectrograms) andassociated windowing functions, or discrete wavelet transforms (such asthe well known Haar wavelet transform). On-probe/off-probecommunications may further be enhanced through improved execution ofcyclic redundancy code (CRC) calculations for use in error detection.

Such user-customized and optimized extensible processor coresadvantageously have a reduced gate count requiring less silicon thancomparable non-optimized cores or multi-purpose (e.g., “CISC”) processordesigns, since the selection of a highly optimized instruction setsubstantially eliminates non-essential functionality during processordesign synthesis and fabrication. With lower gate count, static andswitching power losses are reduced, thereby providing the furtherbenefits of reduced power consumption and lower rates of heatgeneration. Accordingly, with the present invention, the manufacturer ordesigner may advantageously select the appropriate optimized coreconfiguration and instruction set applicable to the anticipated use ofthe endoscopic probe, thereby reducing the required space needed withinthe probe to accommodate the ASIC to the absolute minimum consistentwith the extant or subsequently developed semiconductor fabricationprocess employed, and the power consumed and heat generated thereby.

Additionally, the core 1604 (and in fact the entire SoC device 1600)optionally includes one or more processor “sleep” modes of the type wellknown in the digital processor arts, which allow portions of the coreand/or peripherals to be shut down during periods of non-operation inorder to further conserve power within the device and reduce heatgeneration. For example, the pipeline and memory can be selectively shutdown to significantly reduce power consumption when these components arenot required (e.g., the probe is dormant before activation in vivo). Itwill further be appreciated that the aforementioned sleep modes may bepreprogrammed; e.g., upon the occurrence of (or lack of) a certainevent, such as the passing of a predetermined number of processor clockcycles, falling below a certain battery voltage level, detection ofcertain antigens via the antigen sensor array (FIG. 32), etc.Alternatively, the sleep modes may be actively invoked such as by theuser based on operational parameters, such as when the shutdown of theprobe for a period of time is desirable in order to conserve power forlater activation.

The processor core 1604 of the embodiment of FIG. 16 comprises anextensible RISC processor of the design provided by ARC Internationalplc of Elstree, Herts, UK, although other configurations may be used.The construction of optimized, extended instructions and instructionsets is well known in the processor design arts, and is described, forexample, in U.S. Pat. No. 6,032,253 entitled “Data Processor withMultiple Compare Extension Instruction” issued Feb. 29, 2000, and U.S.Pat. No. 6,065,027 entitled “Data Processor with Up Pointer Walk TrieTraversal Instruction Set Extension” issued May 16, 2000, both or whichare incorporated herein by reference in their entirety.

The SoC device 1600 (including core) design is generated using VHSICHardware Description language (VHDL) in conjunction with design andsynthesis tools of the type well known in the art. An InternationalBusiness Machines (IBM) “Blue Logic™” 0.11 micron Cu-11 ASIC process isused to fabricate the device of the illustrated embodiment, althoughother semiconductor fabrications processes including for example 0.35micron or 0.18 micron may be substituted, depending on the degree ofintegration required. The IBM process further affords ultra-low powerconsumption by the device (1.5 V supply, which reduces power consumptionby more than 50% over comparable 3.3 V devices). It will be recognized,however, that such higher voltage processes and devices may besubstituted consistent with the integration and power requirements ofthe probe.

Furthermore, combinations of discrete components or collections thereofmay also be used consistent with the invention. For example, the SiW1502Radio Modem IC manufactured by Silicon Wave Corporation of San Diego,Calif., is a low-power consumption device with integrated RF logic andBluetooth protocol stack adapted for Bluetooth applications. The chip isa fully integrated 2.4 GHz radio transceiver with a GFSK modem containedon a single chip. The SiW1502 chip is offered as a stand alone IC or,may be obtained with the Silicon Wave Odyssey SiW1601 Link ControllerIC. The SiW1502 form factor is 7.0×7.0×1.0 mm package which is readilydisposed within the interior volume of the probe described herein.

The RF transceiver 1610 and modulator device 1612 used in the embodimentof the SoC 1600 of FIG. 16 a is adapted to generally comply with thewell known “Bluetooth™” wireless interface standard, or alternatively,other so-called “3G” (third generation) communications technologies. TheBluetooth wireless technology allows users to make wireless and instantconnections between various communication devices, such as mobiledevices (e.g., cellular telephones, PDAs, notebook computers, remotemonitoring stations, and the like) and desktop computers or other fixeddevices. Since Bluetooth uses radio frequency transmission, transfer ofdata is in real-time. The Bluetooth topology supports bothpoint-to-point and point-to-multipoint connections. Multiple ‘slave’devices can be set to communicate with a ‘master’ device. In thisfashion, the endoscopic probe of the present invention, when outfittedwith a Bluetooth wireless suite, may communicate directly with otherBluetooth compliant mobile or fixed devices including the subject'scellular telephone, PDA, notebook computer, or desktop computer.Alternatively, a number of different subjects undergoing endoscopicanalysis using the smart probe may be monitored in real time at acentralized location. For example, video data for multiple differentpatients within the ward of a hospital undergoing endoscopic analysisusing the smart probe may be simultaneously monitored using a single“master” device adapted to receive and store/display the streamed datareceived from the various patients. A variety of other configurationsare also possible.

Bluetooth-compliant devices, inter alia, operate in the 2.4 GHz ISMband. The ISM band is dedicated to unlicensed users, including medicalfacilities, thereby advantageously allowing for unrestricted spectralaccess. Maximum radiated power levels from the transceiver 1610 of FIG.16 a are in the mW range, thereby having no significant deleteriouseffect on the physiology of the subject due to radiated electromagneticenergy, especially given the comparatively transient nature of thetransmissions from the transceiver, and the movement of the probe withinthe intestine. As is well known in the wireless telecommunications art,radiated power from the antenna assembly (not shown) of the transceiver1610 may also be controlled and adjusted based on relative proximity ofthe transceiver 1610 (and probe), and/or the relative proximity andlocation of one or more other probe transceivers, thereby furtherreducing electromagnetic whole body dose to the subject.

The modulator 1612 uses one or more variants of frequency shift keying,such as Gaussian Frequency Shift Keying (GFSK) or Gaussian Minimum Shiftkeying (GMSK) of the type well known in the art to modulate data ontothe carrier(s), although other types of modulation (such as phasemodulation or amplitude modulation) may be used.

Spectral access of the device is accomplished via frequency dividedmultiple access (FDMA), although other types of access such as frequencyhopping spread spectrum (FHSS), direct sequence spread spectrum (DSSS,including code division multiple access) using a pseudo-noise spreadingcode, or even time division multiple access may be used depending on theneeds of the user. For example, devices complying with IEEE Std. 802.11may be substituted in the probe for the Bluetooth transceiver/modulatorarrangement previously described if desired. Literally any wirelessinterface capable of accommodating the bandwidth requirements of thesystem may be used.

In yet another embodiment of the invention, the probe utilizes atime-modulated ultra wide-band (TM-UWB) protocol for communication withone or devices external to the subject while the probe is in vivo.Specifically, the probe is fitted with an SoC device similar to thatdescribed previously herein with respect to FIG. 16; however, the SoCdevice of the present embodiment utilizes pulse-position modulation(PPM), wherein short duration “Gaussian” pulses (nanosecond duration) ofradio-frequency energy are transmitted at random or pseudo-randomintervals and frequencies to convey coded information. Information iscoded (modulated) onto the short duration carrier pulses by, inter alia,time-domain shifting of the pulse. For example, a pulse encodes a bit bybeing temporal shifting of the pulse with respect to a reference, suchthat a “late” pulse encodes a “0”, while an early pulse encodes a “1”.This scheme is somewhat akin to the well known frequency shift keying(FSK), wherein two (or more) side-band frequencies are utilized toencode data; e.g., 67 kHz down-shift=0; 67 kHz up-shift=1. TM-UWBdevices have the advantage of ready penetration of various mediums, aswell as ultra-low power consumption and low spectral density, therebyreducing probe power requirements and potential interference with otherdevice, respectively. In one exemplary variant, the TM-UWB device of theinvention comprises a half duplex, 2.0 GHz with variable data rate inexcess of 1 Mbps with no forward error correction (FEC).

The Gaussian monopulse is of the form:V(t)=(t/τ)e ^(−(t/τ)2)Where τ is a time decay constant related to the Gaussian monopulseduration, and center frequency f_(c)=k/τ. The monopulse's bandwidth andcenter frequency are therefore directly related to the monopulse'stemporal width or duration. This approach also shifts the transmissiontime of each monopulse over a significant time interval in accordancewith a pseudo-nose (pn) “hopping” code of the type well known in theart, thereby advantageously distributing spectral density to make thespread. This approach is roughly comparable to frequency hopping spreadspectrum (FHSS) except in the time domain. FIG. 16 b illustrates oneembodiment of the TM-UWB transceiver used in conjunction with theinvention, although it will be appreciated that other configurations maybe substituted. Exemplary devices incorporating TM-UWB componentsincluding the timer, correlator, and digital baseband signal processorand controller units (not shown) are available from IBM Corporation(silicon germanium-based) in the form of a chip set, although it will berecognized that an integrated single device is optimal for theinvention. Additional detail on the implementation of TM-UWB systems isfound in, e.g., “Time Modulated Ultra-Wideband for WirelessApplications”; Time-Domain Corporation, 2000, which is incorporatedherein by reference in its entirety.

Referring now to FIG. 17, another embodiment of the invention isdescribed having a radio frequency identification (RFID) tag 1702installed within or made part of the autonomous smart probe 1700 toprovide a variety of functions, including (i) retention of subject- orcontext-specific data; (ii) capsule inventory and security aftermanufacture; (iii) selective interrogation of probes; and (iv) writingor reading data to or from multiple probes simultaneously. Each of theseaspects are described in greater detail below.

RFID tags are well known in the communications art. The main advantagesof an RFID sensor and tag system over other forms of ID tagging include(a) the orientation of the tag with respect to the sensor is notcritical for a correct read of the tag information; (b) communicationcan occur within comparatively harsh operating environments includingthose present in the intestinal tract of a living subject; and (c) thecommunication range between the sensor and tag can be significant (up toseveral hundred meters) even when the RF frequencies used are within thepower limitations of Federal Communications Commission (FCC) rulesconcerning unlicensed transmitters. Accordingly, RFID technology isuseful for several applications, especially those relating to securityand asset management.

The process of “reading” and communicating with an RFID tag such as thatused in the probe 1700 of FIG. 17 comprises bringing a RFID tag withinproximity to an RFID sensor (“reader”) 1750 which emanates a radiofrequency wake-up field having a limited range. The RFID tag 1702detects the presence of the wakeup field of the sensor 1750, andsubsequently various forms or protocols of handshake occur between thetag 1702 and the sensor 1750 in order to exchange data. All of thiscommunication between the tag and the sensor is performed using RFcarriers of one or more prescribed frequencies. As is well known in theart, so-called “low-frequency” systems operate in the kHz to low-MHzrange (unlicensed). Low frequency systems are generally low cost andcomplexity and have comparatively limited range, but are attractivesince the low frequency energy tends to suffer low losses from materialslike metal, polymers, tissue, and the like. High-frequency systemsoperate in the low-MHz to GHz range (often licensed). High-frequencysystems in general have greater range, but are more directional.Additionally, the performance of these high frequency tags may beadversely affected by electromagnetic radiation or proximate metallicobjects.

Additionally, RFID tags are generally categorized as being “active”(i.e., carry an associated power source for operation of the on-tagintegrated circuit, and are capable of spontaneous transmission afterreader interrogation), or “passive” which utilizes incident RF energy(from the reader, for example) to generate electrical energy for use bythe IC, and transmission. Passive tags are highly energy efficient, andrequire only a small amount of electrical power to function.

In the present application, due to the premium on space within the probe1700, a small antenna and package form factor (less than about 10 mmacross) is required. Based on the foregoing considerations, the presentembodiment of the invention utilizes a high frequency (e.g., 15 GHznominal) miniature passive tag having a miniature monopole antenna 1706of the type well known in the art, although it will be recognized thatactive tag architectures, lower or higher frequency systems, andalternate antenna configurations (such as “FIG. 8” loop, etc.) may beused depending on the particular application. A nominal frequency of 15GHz is used as the carrier for the system, 10 mm corresponding to aboutone-half wavelength at that frequency.

The RFID tag 1702 of the present invention further includes anintegrated circuit (IC) device 1705 including a transceiver section 1707and processing logic 1709, as well as an integrated random access memory(RAM) device 1708 of the type commonly available with such devicesadapted to store a plurality of data bytes such as data correlating toan individual subject, date of administration of treatment, socialsecurity number, and the like. The memory device 1708 may also comprise,without limitation, PROMS, EPROMS, EEPROMs, UVEPROMS, SRAMs, DRAMs,SDRAMS and ferroelectric memory devices. As illustrated in FIG. 17, thememory 1708 of the present embodiment is effectively independent of theon-probe memory 1751 (e.g. DSP “flash” or discrete memory previouslydescribed herein with respect to FIG. 10). In this capacity, theconstruction of the probe 1700 is simplified, and less complex or even“off the shelf” RFID devices meeting the physical space limitations maybe used with little or no adaptation.

It will be recognized, however, that if data communication between theRFID memory 1708 and other memory devices or signal processing disposedon-probe or off-probe is desirable (such as described with respect tothe alternate embodiment(s) below), such communication may be affectedvia techniques well known in the electronic arts. The present inventionfurther contemplates, in an alternate embodiment, the integration of theRFID “tag” components including memory into a single silicon orsemiconducting die, such as in the form of the aforementioned ASIC. Suchembodiment has the advantage, inter alia, of further conserving on spacewithin the probe.

In yet another embodiment, the RFID tag is distributed on one or moresurfaces of the probe. See for example the “Bistatix™” RFID devicesmanufactured by Motorola Corporation, which utilize a very thin and lowcost substrate employing printed circuit technology. Hence, by employingthe Bistatix technology within the RFID tag of the present invention,the RFID tag may be disposed on any surface within the probe, such asthe interior of the housing, on an unused section of PCBA, etc.

In operation, the tag “reader” 1750 of FIG. 17 interrogates the probe1700 and RFID device 1702 at its designated frequency, causing the tagto “wake” and initiate communications protocols disposed within the tagmemory 1702. Once such protocols are established, the reader transmitspreformatted data representative of the parameters desired to be loadedinto the RFID memory device 1708. For, example, prior to a given subjectswallowing or having the probe introduced endoscopically, the tag memory1708 is encoded with the subject's name, SSN, and date of administrationvia signals received from the reader 1750 via the antenna 1706 andtransceiver section 1707 and processing logic 1709.

In yet another embodiment, the tag 1702 is coupled to themicrocontroller IC 520 (FIG. 5) of the probe, thereby allowing the tagto “wake up” the probe indirectly (instead of using the aforementionedtransceiver 1610 of the embodiment of FIG. 16, or alternatively aninductive/capacitive signal). In this fashion, the probe may becompletely powered down until it is awaken by the tag 1702, therebyproviding significant power savings prior to in vivo operation. Suchpower savings are even greater than those provided by the processor“sleep mode” previously described with respect to FIG. 16, in that whenusing the RFID tag 1702 wake up feature, the digital processor core 1604of the ASIC may be completely shut down, including clock generator,pipeline, and (static) memory. Such complete shut down is possible sincethe passive tag generates a small amount of electrical power, on theorder of a few mW, sufficient to re-initiate processor (and probe)operation on the battery or other power source providing electricalpower after wake-up. It will be recognized, however, that thetransceiver 1610 may alternatively be constructed to generate therequired electrical power upon “interrogation” by a complementary RFtransmitter.

The RFID tag 1702 of the embodiment of FIG. 17 has further utility forconducting inventory of “smart” probes after manufacture. Since eachprobe carries it's own tag, each capable of uniquely identifying itself(whether by unique frequency assignment, or data encoded on the tagmemory 1708 and transmitted to the reader), rapid reading of a pluralityof tags disposed in close proximity to one another is possible. Forexample, since the probes may be a valuable and easily pilferablecommodity, regular inventory can be rapidly accomplished using theaforementioned RFID technology.

In yet another application, the foregoing unique identificationcapability of the tag 1702 coupled with the range of the high-frequencyantenna system allows for the selective interrogation of the tag so asto load information, retrieve data, or initiate probe functions (such aswake up) while in proximity to other similar devices. For example, it iscontemplated that the smart probe 1700 of the invention will be used in,inter alia, hospitals or other care facilities where a number ofsubjects undergoing various types of treatment are present. Suchtreatment likely includes several patients for which the smart probe1700 has been administered. Rather than having to individuallyinterrogate each tag by physically disposing it local to acommunications device or reader 1750, the caregiver may selectivelyinterrogate any tag within range of a central reader (not shown) toupload information (such as name, SSN, etc.), and/or induce wake-up ofthe tag and its associated probe, and the collection of data, oralternatively conduct of other types of operations such as the deliveryof medication, radioisotope therapy, tissue biopsy, or any other numberof probe-related tasks as described in detail herein. Such centralreader may further be programmed to automatically initiate and monitorsuch activities, such as through a software routine running on aprocessor disposed within the central reader. Many other control schemesare possible (e.g., upon the occurrence of predetermined events, thepassage of time, a signal generated by a miniature accelerometerdisposed within the probe adapted to sense motion of the subjectindicating that they are awake/ambulatory, etc.), and may be used inplace of or in combination with the techniques previously described. Theconstruction of such miniature accelerometers is well known in theelectronics arts; see, for example, U.S. Pat. No. 5,205,171 entitled“Miniature Silicon Accelerometer and Method” issued Apr. 27, 1993, andincorporated by reference in its entirety herein.

In another embodiment, the tag reader 1750 is placed within the home oron the person of the subject receiving treatment (in a portableconfiguration, such as a hand-held reader unit provided to the subjectprior to treatment). The reader 1750 is linked to a central control ormonitoring facility via any available communications channel havingsufficient bandwidth including analog (“copper”) telephone, wirelesstelephone or other wireless service, optical network, inter- orintra-network, local or wide area network, satellite communicationslink, etc., as is well known in the art. Accordingly, the centralfacility can initiate probe wakeup or other functions remotely withinthe subject's home by prompting the reader 1750 to interrogate the RFIDdevice 1702. The reader can further be programmed to repeatedly transmitthe wake-up interrogation signal until confirmation of tag wake-up,thereby assuring that subject monitoring, data collection, or otherdesired functions are accomplished, regardless of the subject's physicallocation at time of first transmission by the central facility.Eventually, the subject (and tag 1702) will pass proximate to the reader1750 such that wake-up is accomplished. Accordingly, the reader 1750 caneven be configured as a portable personal device, such device beingcarried on the subject's person during the monitoring period.

It will be appreciated that many different variations and combinationsof the foregoing radio frequency communications apparatus and methodsmay be employed consistent with the invention; such different variationsand combinations being too numerous to describe herein. All suchvariations and combinations, however, are easily recognized and withinthe possession of those of ordinary skill.

Radiation Therapy Apparatus and Method

Referring now to FIGS. 18 a through 18 h, an improved apparatus andmethod for delivery of radionuclides to tissue within the intestinaltract of a living subject are disclosed. In one exemplary embodimentshown in FIGS. 18 a-e, the apparatus 1800 comprises, for example, a“smart” probe according to the invention as previously set forth hereinwhich has been further adapted to carry and expose a radioactive source1802 for emitting ionizing radiation at a prescribed location within theintestine. The source 1802 may comprise a gamma ray, beta particle,alpha particle, and/or even neutron emitting material, depending on theneeds of the particular application as described in greater detailbelow. The source 1802 is shielded while carried in the probe by aretractable shield element 1804. The shield element 1804 of the presentembodiment comprises a high-density metallic annular element fabricateddisposed on a micro-ball track assembly 1806, the entire assembly beingcontained within the rear portion 1807 of the outer housing 1801 of theprobe 1800. Complete containment of the shield element 1804, source1802, and associated mechanisms within the probe 1800 provides a numberof potential advantages, including (i) prevention of externally appliedfrictional forces or even portions of the epithelial tissue, frominterfering with the retraction and restoration of the shield element1804; (ii) prevention of gastric or intestinal fluids from entering theprobe 1800; (iii) the ability to rotate the shield element(s) and/orsource 1802 with respect to one another, thereby providing for selectivecollimation or “pointing” of the emitted quanta or subatomic particlesin vivo. It will be recognized, however, that for alpha radiationsources (and potentially certain sources emitting low energy betaparticles), the intervening portion of the outer housing 1803 of theprobe 1800 will substantially mitigate any dose to the adjacentintestine wall. Accordingly, for such sources, the probe is optionallyconfigured with selectively controlled “windows” 1805 or aperturesformed in the outer housing 1801 allow alpha particles and otherradiation unencumbered passage from the source 1802 to the targetintestinal tissue, as illustrated in FIG. 18 b. In one variant, thewindows 1805 are covered by a series of complementary tabs (not shown)disposed on the periphery of the shield element 1804, coincident withthe windows 1805. When in the restored position, the tabs cover thewindows to mitigate the ingress of intestinal tissue, fluid, or othermaterials there through. When the shield element is retracted, thewindows 1805 are uncovered.

Furthermore, it will be recognized that the thickness and composition ofthe outer housing 1801 in the region directly radial to the source 1802may be adjusted, in conjunction with the source strength andradionuclide selected, to effectuate the desired spatial, temporal, andenergy irradiation profiles. For example, if it is desired to expose theselected region of the intestine only to comparatively high energy betaparticles from a source having multiple energy alpha and beta particleemissions, the thickness and/or constituent material of the outerhousing may be selected such that effectively all alpha radiation, aswell as low energy beta particles, are shielded by the relevant portionof the outer housing 1801. Accordingly, only the more energetic betaparticles (and any gamma, neutrino, or other penetrating radiationemitted by the nuclide(s)) will exist in sufficient quantity outside theouter housing to effectuate the desired therapeutic exposure. Theselection of materials to attenuate various constituent types andenergies of radiation to achieve a desired spectral distribution is wellknown in the radiologic arts, and accordingly is not described furtherherein.

As shown in FIGS. 18 c and 18 d, the shield element 1804 of the probe isdisposed on the micro-ball track assembly 1806 such that the shieldelement may be dislocated or translated longitudinally along the axis1837 of the probe when retracted. The micro-ball track assembly 1806comprises three tracks 1819 with races 1851 and associated bearing balls1820 which are mounted so as remain rigid and engage the shield element1804 during all phases of retraction of the latter. The assembly 1806optimally is an ultra low friction device, thereby allowing guidance andmovement of the shield element 1804 with a minimum of electrical powerconsumption. It will be recognized, however, that other arrangements forguiding and supporting the shield element 1804 may be used consistentwith the invention, the present embodiment being merely exemplary. Thetracks 1819 are further equipped with a series of raised stop elements1853 which are disposed at either end of the portion of the tracks forwhich travel of the bearings 1820 is desired; the stops act to limit thelongitudinal translation of the bearings 1820 within the races 1851 suchthat the bearings do not roll out of their races into the volume of theprobe during all orientations of the probe with respect to the localgravitational field and all positions of the shield element 1804 duringuse (i.e., fully retracted, partially retracted, or closed).

A shown in FIG. 18 a, the retraction mechanism 1809 of the presentembodiment comprises a miniature solenoid assembly 1810 of the type wellunderstood in the electromagnetic arts. See for example, U.S. Pat. No.5,907,339 entitled “Ink jet printhead having solenoids controlling inkflow” issued May 25, 1999, and U.S. Pat. No. 6,092,784 entitled “Coilassembly useful in solenoid valves” issued Jul. 25, 2000, bothincorporated by reference herein, which describe the construction ofminiature solenoid valves. The solenoid assembly 1810 of the presentembodiment includes a substantially cylindrical ferromagnetic coreelement 1812 which is coupled mechanically to the primary shield element1804, and polymer-insulated (dielectric) electrically conductivesolenoid coil element 1814 which is disposed around at least a portionof the ferromagnetic core 1812. As is well known in the art, theapplication of an electrical current through the coil element 1814generates a magnetic (B) field, which, upon interaction with themagnetic lines of flux generated by the ferromagnetic core element 1812,induces a generally longitudinal displacement force (F) 1815 as shown inFIG. 18 c. As is well known in the electromagnetic arts, the force Fgenerated by the solenoid is given generally by:F=qV×B

Where:

F=resultant force vector

q=charge

V=charge velocity vector

B=magnetic field vector

x=vector cross product

A restoring spring 1817 having a preselected spring constant is disposedat the rear portion of the probe and in communication with the rear end1818 of the shield element/core assembly to urge the shield 1804 andcore 1812 back into position in the event of a loss of electrical power,thereby causing the probe 1800 to “fail safe” with respect to theradiation source 1802. This arrangement also has the benefit ofobviating the need for electrical power to return the shield element1804 to its nominal (i.e., non-retracted) position. However, the desireto protect against unwanted exposure in the event of a power or othertype of device failure must be balanced against the comparatively energyconsumption required to displace the shield 1804 and core 1812 againstthe restoring spring 1817 for any period of time. As is well known inthe mechanical arts, the spring force applied generally obeys thefollowing relationship:F=kxWhere:

F=restorative force exerted by the spring

k=spring constant (F/displacement)

x=linear displacement.

According to this relationship, as the shield element is displacedfurther from it's normal position (little or no compression of thespring), the force necessary to overcome the restorative spring forceincreases generally linearly. Therefore, progressively increased currentflow through the solenoid coil is required to displace the shieldelement further.

The solenoid coil 1814 of the illustrated embodiment is physicallyretained and suspended around the core 1812 by an annular supportelement 1870 which is attached to the individual tracks 1819 of theassembly 1806 via a plurality of respective support members 1872. Thecoils 1814 is fixed with adhesive to the interior walls of the annularsupport 1870 such that no interference between the core 1812 and thecoils 1814 occurs when the shield element 1804, disposed on the ballbearings 1820 of the tracks 1819, slides along the axis 1837 of theprobe under magnetically induced force.

Hence, if power consumption is especially critical (such as in the caseof where probe power is supplied by an on-probe battery), othersafeguard mechanisms may be substituted or used in concert. For example,the type and strength of source 1802 may be selected so as to mitigatewhole body gamma dose, such as by choosing a nuclide having a low energygamma and low gamma yield in relation to emitted particulate radiationsuch as alpha or beta. Similarly, the half-life of the nuclide may beselected such that is will rapidly decay to a “safe” level irrespectiveof probe operation. Other techniques may also be used, such by using afail-safe mechanism which does not require significant electrical powerconsumption (e.g., pressurized gas or other pre-stored potential energy,as in the form of a compressed bias spring). Furthermore, interlocklogic functions of the type well known in the art may be applied toretraction of the shield element 1804, such as for example (i) thepassing of a minimum or maximum amount of time as measured by theprocessor clock (described below), or (ii) the probe being in certaindesired orientation within the subject's intestine (such as may bedetermined by a liquid metal or other similar type of switch), or evenother criteria.

The retraction and release of the shield element 1804 is controlled viathe on-probe processor/microcontroller 520 as is well known in theelectronic arts. Control via the processor/microcontroller may bestructured in any number of ways, including those generated internallyto the probe (such as having the microprocessor “count” using itsinternal clock signal generator for a prescribed period of time, andthen automatically retracting the shield 1804 via the microcontroller520,) or by receipt of an external inductive, capacitive, radiofrequency, magnetic, or other initiating signal to a correspondingsensor within the probe, such as a 2.4 GHz radio frequency controlsignal received by the SoC transceiver element 1610 (“control event”).Alternatively, the probe shield 1804 may be controlled by way of othersensor devices mounted on the probe, such as the molecular sensor array3202 described subsequently herein with respect to FIG. 32. For example,electrical conductance (or resistivity) readings obtained from themolecular sensor array 3202 may be used to trigger retraction of theshield element 1804, such as when it is desired to irradiate tissue onlywhen in the presence of certain molecules within the intestine. It willbe recognized that a plethora of other control schemes may be employedconsistent with the invention, all such control schemes being within thepossession of those of ordinary skill in the art when taken in concertwith this disclosure.

The power supply circuitry of the probe may also optionally be adaptedto generate high discharge rates of the power supply (and accordinglyhigh currents through the solenoid coil) such as by using diode currentlimiting devices with high threshold currents of the type well known inthe electrical arts, thereby allowing for the generation of sufficientmagnetic field strength to overcome an increased restoring spring force,the increased spring restoring force provided additional safety marginfor return of the shield element 1804 to its nominal (closed) position)upon completion of irradiation or power failure. The tradeoff in suchcircumstance is, however, the reduced longevity of the on-probe powersupply. As will be appreciated, the structural capacitor described belowwith respect to FIG. 27 may also be utilized for this purpose.

As shown in FIG. 18 f-18 g, the radiation source 1802 may also becollimated in the circumferential dimension (e.g., around one or moreportions of its circumference), so as to form discrete solid angles 1831of radiation emission with respect to the source 1802. Such collimationmay be accomplished using any number of techniques, including (i) asegregated source construction technique wherein the radioactive sourceregions 1833 are dispersed around the circumference of the sourceelement 1802, as illustrated in FIG. 18 h; (ii) a secondary shieldelement 1835 disposed around the source which blocks certain angles ofemission, as illustrated in FIG. 18 g; or (iii) by constructing theshield element 1804 such that when retracted, only certain portions ofthe circumference of the source 1802 are exposed. Furthermore, it willbe appreciated that the relative angular position of the source 1802,secondary shield element 1835 (FIG. 18 g), or primary shield element1804, may be made alterable, such as through use of motor assemblyhoused within the probe (not shown) which rotates the source, secondaryshield 1835, or primary shield 1802 around the axis 1837 of the probe,such that the operator may adjust the orientation of the uncollimatedradiation beam to the desired relative orientation based on the positionof the probe within the intestine. In this fashion, the operator mayeffectively steer the radiation beam with the probe in vivo if desired.The construction and operation of miniature motor assemblies (e.g.,direct current commutated motors) such as those referred to herein arewell known in the electromechanical arts, and accordingly will not bedescribed further herein.

The physical and chemical properties of the radionuclide source 1802 areimportant criteria in its selection for radiotherapy according to themethod described herein. Specifically, the type of radioactive emission(e.g., beta particle, alpha particle, gamma ray, etc.) must beconsidered with respect to the target tissue.

Alpha particles are essentially doubly-ionized Helium nucleii. They havea high kinetic energy (KE) transfer, and are effective in cell killingto a range of several cell diameters (up to approximately 100 microns).Due to their comparatively high mass and charge, alpha particles arecompletely attenuated by even a few mils of a low density shieldingsubstance, and the likelihood of an alpha particle passing through acell and not damaging a critical structure is roughly 4 to 10 timeslower than for beta or gamma radiation. This relationship is oftenreferred to as “quality factor”. Generally speaking, a comparable levelof tumor ablation (at least with respect to superficial regions of thetumor) can be achieved with lower alpha radiation doses as with higherdoses. Another advantage of alpha emitters is their ability to createionization in the absence of oxygen. This is an important advantage inthe treatment of tumors that have areas of hypoxia.

One of the disadvantages of alpha emitters is their relatively limitedselection. Astatine-211 has the disadvantage of requiring a cyclotron toproduce it. This, coupled with its 7.2 hour half-life, makes its usesomewhat impractical. Alternatively, Lead-212 has a 10.6 hour half-lifeand decays by beta emission to ²¹²Bi. Bismuth-212 has a 1 hour half-lifeand decays by beta and alpha emission to stable ²⁰⁸Pb. Lead-212 isproduced from Radium-224 which has a 3.6 day half-life.

Beta particles (essentially ejected electrons or positrons) are lesseffective at ionizing, and also have a significantly greater range inair than alpha particles. Not nearly as penetrating as gamma rays orX-rays, beta particle flux (dependent on energy) may be effectivelyattenuated with only a few mils of a high density substance, such asmost metals.

Additionally, gamma-ray energies and abundances should also beconsidered when selecting a source 1802. In comparison to alpha and betaparticles, gamma rays (even those at low energy) are highly penetrating,and accordingly add significantly to the whole-body radiation dose ofthe subject when used for radiation therapy.

Numerous beta emitters exist, offering a broad selection of particleenergies and chemical properties. Many courses of therapy have utilized¹³¹I, largely due to its ready availability at moderate cost, andrelative familiarity ¹³¹I has a physical half-life of 8.04 days, maximumbeta energy of 0.8 MeV, average beta energy of 0.2 MeV, and isconsidered a medium-range beta emitter (mean range between 200 μm to 1mm in soft tissue) with a maximum range of about 1.5 mm. However, thegamma yield of ¹³¹I (0.36 MeV average) results in higher total bodydoses away from the tumor location, thereby contributing to subjecttoxicity.

Yttrium-90 (⁹⁰Y) may also be useful in certain applications because ofits favorable characteristics, which include a 64 hour half-life and anintermediate beta energy (2.3 MeV).

Rhenium-186 has been used for radioimmunotherapy. The energycontribution from gamma rays of ¹⁸⁶Re is 137 keV with only about 9%yield, which provides a lower dose to the whole-body than with ¹³¹I.X-rays produced by ¹⁸⁶Re are low energy radiations (59-73 keV, about 9%yield), contributing only marginally to whole body dose.

It will be recognized that while the selection of radionuclide must becarefully considered, any number of different nuclides (including, forexample, 1²³I, ¹²⁵I, ¹³¹I, ³²P, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁹⁷Ru, ²¹¹At, ¹⁷⁷Lu,⁹⁰Y, ¹⁸⁶Re, ²¹²Pb, ¹⁹⁸Au and ²¹²Bi) may be used alone or in combinationas the source 1802 of the invention. Additionally, the “source” used inthe probe may be paramagnetic or supramagnetic and/or facilitatediagnostic imaging procedures including gamma scintigraphy, singlephoton emission computerized tomography (SPECT), positron emissiontomography (PET), nuclear magnetic resonance (NMR), or magneticresonance imaging (MRI), such techniques being well known in the medicalimaging arts. For example, the group consisting of elements 26-30 (Fe,Co, Ni, Cu, Zn), 33-34 (As, Se), 42-50 (Mo, Tc, Ru, Rh, Pd, Ag, Cd, In,Sn) and 75-85 (Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po, At).

Referring now to FIGS. 19 a-19 c, a second embodiment of theradiotherapy apparatus is described. As part of this second embodiment,a plurality of ligands “tagged” with radionuclides 1902 are carriedwithin a repository or container 1904 within the probe 1900 until thedesired location within the intestinal tract is reached. The selection,production, and use of such exemplary tagged ligands is described indetail in various publicly available sources including, for example,U.S. Pat. No. 5,902,583 entitled “Genetic Induction of Receptors forTargeted Radiotherapy” issued May 11, 1999, which is incorporated hereinby reference in its entirety.

Certain compositions may be used consistent with the invention toprovide delivery of therapeutic compounds. The molecules are attached toa substance to be delivered thus enabling the substance to be deliveredspecifically to the intestine upon administration of the conjugate viathe smart probe. In the intestine, these compositions bind to theintestinal surface resulting in delivery and/or long-term presence ofthe therapeutic compound at the intestinal lining. For example, thecarboxy terminal (C tail) region of bile salt-activated lipase (BAL), orfunctional equivalents thereof, (C-tail peptides) may be used in thismanner, as described in U.S. Pat. No. 5,821,226, entitled “BAL C-taildrug delivery molecules” to Tang, et al, issued Oct. 13, 1998,incorporated herein by reference in its entirety

Receptor sites on the tumor cell membrane or other affected locationswithin the intestinal epithelium, which are specifically targeted by theligands, receive the tagged ligands, the radiation emitted therebyproceeding to ionize tumor cell material via emitted beta, alpha, gamma,or neutron radiation until decay or evacuation of the radionuclide. Suchapproach further permits spatial localization of the radionuclide. Suchlocalization may occur with certain receptor/ligand interactions, asdescribed in greater detail below.

The container 1904 of the probe of FIG. 19 a is constructed so as toretain a sufficient volume of the ligands 1902 in solution, andselectively release the ligand solution into the intestinal tract uponassertion of a command from the microcontroller 502 of the probe 1900,such command being initiated either internally from the digitalprocessor 1604, or externally, via a communication channel establishedbetween an external device and the probe (e.g., a radio frequency,inductive, capacitive, or ultrasonic signal). The ligand solution in thepresent embodiment is expelled due to the backpressure generated by astored volume of compressed inert gas (e.g., N₂) disposed within a gaschamber 1908 in the cavity of the probe 1900. The gas chamber may befabricated from any material of sufficient strength and dimension toboth fit within the dimensional confines of the probe 1900 and withstandthe required pressure (on the order of a few psi). The Tefzel outerhousing is utilized in the present embodiment, due to its light weight,low cost, relative ease of molding, and strength. The gas chamber 1908alternatively may be formed as a separate component.

The probe 1900 of the illustrated embodiment is somewhat increased insize over other embodiments described herein (i.e., approximately 15 mmin diameter, and roughly 50 mm long, providing an “empty” internalvolume of roughly 8,500 mm³ after accounting for housing wall thickness)in order to accommodate the volumes of pressurized gas and ligandsolution in addition to the necessary communication, power, and controlcomponents. In that 1000 mm³=1 cc, the volumetric delivery capacity ofthe probe 1900 is fairly limited; roughly on the order of 2 cc. However,it will further be recognized that the “trailer” configuration (i.e.,use of two probe housings coupled via an umbilical) as described hereinwith respect to FIG. 34 may also be readily adapted to providepressurized gas storage and/or ligand solution storage in the event thatmore on-probe capacity is required, or alternatively a smaller probediameter is necessitated (such as for smaller subjects).

A system of sealed, rupturable polymeric diaphragms 1910 a, 1910 b areemployed in the embodiment of FIG. 19 a between (i) the gas chamber 1908(if present) and the container 1904, and (ii) the container 1904 and theexterior of the probe 1900, such that upon controlled rupture of thefirst diaphragm 1910 a, the comparatively high gas pressure resident inthe container 1904 is applied to the ligand solution 1902 in thecontainer 1904, which is ultimately expelled via the second diaphragm(s)1910 b to the exterior region 1911 of the probe 1900. The rate ofpressurization of the container 1904 is controlled (limited) by the sizeof the diaphragm orifice 1912, which is purposely chosen to have a verysmall diameter (on the order of 2 mm). This feature advantageouslymitigates the pressurization rate of the container 1904, therebylimiting the energy with which the outer diaphragm(s) 1910 b and ligandsolution are dislocated/ejected from the probe, thereby eliminating theopportunity for unintended trauma to the intestinal epithelium or othertissues.

In the illustrated embodiment, the interior diaphragm 1910 isselectively and controllably ruptured via the application of anelectrical current to a conductive filament 1913 running through thediaphragm. The filament 1913 is provided current via a set of conductivetraces 1921 formed within the housing of the probe 1900. The conductivefilament 1913 is constructed from very fine gauge (e.g., 38 AWG)nichrome or similar wire which results in a weakening of the polymericmaterial of the diaphragm in the immediate region 1914 of the filament1913 due to localized heating of the filament from the comparativelyhigh electrical current induced by the low electrical resistance of thefilament 1913 and the lack of any other resistive, inductive, orcapacitive elements in the filament circuit. The diaphragm 1910 a mayalso be scored or weakened in the selected regions such that rupture ofthe diaphragm is assured upon application of a minimal electricalcurrent to the filament 1913. The filament 1913 may also be coated witha minute amount of chemically active substance which reacts with thediaphragm material or alternatively generates heat chemically (e.g., anon-toxic “igniter”) to aid in rupturing the diaphragm 1910 a.

In another variant, the inner diaphragm 1910 a is obviated through theuse of the aforementioned igniter material disposed around the filament1913, the combination forming a pressure barrier upon manufacture whichseals the small diameter of the aperture. When the igniter material isactivated, the chemical reaction consumes the igniter material andevolves significant heat, thereby dissolving the pressure seal andallowing the pressurized inert gas to flow through the aperture.

Advantageously, the filament 1913 may also be combined with or embodiedas the conductive-plane carbon fiber filaments present within thepolymer matrix composite housing material of the embodiment of FIG. 27(described below). Specifically, one or more carbon fibers present inthe matrix may be used to conduct electrical current to and from thefilament 1913 of the diaphragm, thereby obviating the need for separatemetallic conductors or traces 1921.

The outer or second diaphragm(s) 1910 b is constructed so as todislocate immediately (i.e., under a predetermined differential pressureacross the secondary diaphragm, ΔP) from the retaining aperture 1917upon the application of the gas chamber pressure to the ligand solutionwithin the container 1904 as shown in FIG. 19 b. The outer diaphragm(s)1910 b are constructed from a biologically inert material which may besoluble, such as the aforementioned “gel cap” material. If soluble, thediaphragm is of sufficient thickness and composition such thatdissolution is prevented during the travel of the probe throughout theintestine, thereby preventing unwanted leakage of the ligand solution.After dislocation, the diaphragm(s) 1910 b is/are dissolved by thesubject's intestinal chemistry, or alternatively expelled. Note thatuntil the inner diaphragm 1910 a is ruptured, the ligand solution 1902resides within the container 1904 at roughly atmospheric pressure, hencethe differential pressure on the second, outer diaphragm 1910 b isminimal.

Additionally, the aperture 1917 of the outer diaphragm(s) 1910 b may bemade somewhat recessed and oblique to the intestine wall as shown inFIG. 19 c, thereby minimizing the chance of any localized trauma to theregion of the intestine wall or epithelium immediately adjacent to theouter diaphragm(s) 1910 b during rupture, and subsequent expulsion ofthe ligand solution 1902. This arrangement also tends to preclude theintestinal wall from obstructing the aperture(s) 1917, therebynecessitating a greater pressure to expel the ligand solution.

Inert gas is utilized in the present embodiment to avoid any potentialtoxicity to the subject due to the expulsion transient. Additionally,the pressure and volume of the gas chamber, and the cross-sectional areaof the diaphragm(s) 1910 a, 1910 b, are optionally selected so as toeliminate any chance of rupture of the intestine wall at large due toinadvertent release or discharge of the gas chamber into the intestinalcavity (as opposed to via the diaphragms 1910 a, 1910 b as describedabove). Specifically, the cross-sectional area of the diaphragms 1910,relative volumes of the gas chamber 1908 and container 1904, and gaschamber pressure are selected such that the PV product of thepressurized gas will dislocate or rupture the diaphragms and expel atleast a portion of the ligand solution into the intestinal volume, yetnot pressurize the intestine to any significant degree. Calculations insupport of such selection are well known in the mechanical arts, andaccordingly not detailed herein. A pressurization port 1990 is alsoprovided to permit charging of the chamber 1908 externally beforeadministration.

Pressurized gas is chosen as the motive force of the present embodimentso as to reduce the complexity of, and electrical loading on, the probewhile in vivo; specifically, the potential energy stored in the form ofpressurized gas substantially obviates the need for other electricaland/or mechanical means to deploy or discharge the ligand (or other)payload. Additionally, the use of rupturable or dislocating diaphragmsobviates the complexity (and space requirements) associated with valvingor other types of regulation mechanism, although it is conceivable thatsuch latter arrangements may be compatible with certain configurationsof the present invention within the constraints of the available space.

Alternatively, in yet another variant, a minute amount of a gasgenerating compound (such as, for example, that described in U.S. Pat.No. 6,073,962 entitled “Gas Generant” issued Jun. 13, 2000, incorporatedherein by reference in its entirety, or alternatively a complex oftransition metals of an aminoalazol, carbodihydrazide, or sodiumazide-based compounds) is disposed behind a non-rupturable diaphragm(not shown) or “bag” and separated from the ligand solution 1902. Thegas generating compound is ignited via electrical current from the powersupply of the probe (via a control signal generated by themicrocontroller 502), thereby increasing the pressure on the outerdiaphragm 1910 b such that the latter is dislocated or ruptured.Toxicity to the subject may be avoided, inter alia, through sealing ofthe diaphragm/bag (even after inflation), and/or through carefulselection of a non-toxic gas generant.

In an alternative embodiment, two non-toxic reactants capable ofproducing an exothermic or gas-evolving reaction having non-toxicbyproducts are mixed, such as common acetic acid and sodium bicarbonatecombined to produce carbon dioxide, according to the following reaction:

The reactants are selectively mixed via rupture of a diaphragm similarto that previously described herein which is induced by an internally orexternally generated command signal (such as that produced by theaforementioned microcontroller upon receipt of an RF command via theon-probe transceiver, or alternatively the occurrence of a predeterminedevent) to evolve gas within the fixed volume mixing chamber (not shown),which comprises the combined volume of the two reactant chambers. Theheat and/or gases evolved by the exothermic reaction increase thepressure within the chamber, which is used to expel the ligand solutionfrom the probe through distension of an elastomeric bladder disposedbetween the mixing chamber and the ligand container.

As yet another alternative, the microchip release methodology providedfor in U.S. Pat. Nos. 5,797,898 entitled “Microchip Drug DeliveryDevices” issued Aug. 25, 1998, and 6,123,861 entitled “Fabrication ofMicrochip Drug Delivery Devices” issued Sep. 26, 2000, both assigned toMassachusetts Institute of Technology, both incorporated by reference intheir entirety herein, and described in detail below, may be used inconjunction with the smart probe of the present invention to effectuaterelease of the tagged ligands 1902. Specifically, in one embodiment, theetched substrate is disposed at or near the surface of the probe, suchas by being embedded into the outer housing, and the contents ofreservoirs of the substrate released at the desired point during probetravel within the intestine. As yet another alternative, the container1904 and enclosed ligand solution 1904 may be directly pressured aboveatmospheric (or prevailing intestinal pressure, if different thanatmospheric) using the inert gas previously described, or othercomparable mechanism. As will be readily appreciated by those ofordinary skill, such methodology may also be coupled with the use of asingle outer diaphragm 1910 as previously described, the aforementioned“microchip” release apparatus, or even a diffusion membrane which allowsfor selective diffusion of the tagged ligands through its thickness intothe intestinal tract. Many configurations and combinations of theforegoing techniques, and in fact many others, may be used consistentwith the present invention, all such configurations and combinationsfalling within the scope of the claims appended hereto.

Referring now to FIG. 20, a third embodiment of the apparatus forproviding radiation therapy to a living subject is disclosed. In theembodiment of FIG. 20, the probe 2000 is adapted to contain a pluralityof nanostructures 2001 (e.g., C-60 fullerenes, aka “Bucky-balls”, andannular graphite film structures, or “nanotubes”) which each include oneor more “captured” atoms or molecules of a desired radionuclide withinthe cavity of the nanostructure structure.

“Buckyballs”, Nanotubes, and Other Nanostructures

Besides graphite and diamond, carbon exists as C-60 in structuresprimarily composed of hexagons and heptagons whose edges are formed bythe carbon-carbon bonds. The first and best known of these structures isthe Buckminster-Fullerene C-60 “bucky-ball”. The bucky-ball is composedof 20 hexagons and 12 heptagons arranged in the same way as the ‘facets’on a soccer ball (i.e., truncated icosahedron). See FIG. 20 a.

Each carbon atom in an all-carbon C-60 fullerene network is bonded tothree other carbon atoms. The C-60 fullerene network forms a moleculewith a cage-like structure and generally aromatic properties. All-carbonfullerene networks contain even numbers of carbon atoms generallyranging from 20 to 500 or more. Larger fullerenes are known as well,with many hundreds of carbon atoms bonded together in a fullerenenetwork. Additionally, “nested” fullerenes (hyperfullerenes) may beprepared wherein one closed fullerene structure is contained within asecond larger closed fullerene structure, these structures beingcontained in turn within a larger closed fullerene structure. Whilethese hyperfullerene spheroidal carbon molecules are considered to bethe most stable forms of fullerenes in terms of cohesive energy percarbon atom, other shapes are possible.

Another useful aspect of the carbon fullerene (e.g., C-60) is theability to dispose one or more entities within the “cage” of themolecule, as shown in FIG. 20 b. The truncated icosahedron structureproduces a cavity or void within the fullerene, which, depending on thefullerene configuration, may act to contain or house and protectmolecules contained therein. Such contained molecule may be capturedwithin the fullerene until one or more carbon-carbon bonds are broken,thereby opening a “window” for the extraction or escape of the molecule.Numerous mechanisms for breaking carbon-carbon bonds within a fullereneare known to those of ordinary skill, and accordingly will not bedescribed in detail herein.

The production of C-60 or other fullerene structures containing“captured” molecules or atoms (including radioactive species) is alsowell known. See for example, U.S. Pat. No. 5,350,569 entitled “Storageof Nuclear Materials by Encapsulation in Fullerenes” issued Sep. 27,1994, and U.S. Pat. No. 5,640,705 entitled “Method of ContainingRadiation Using Fullerene Molecules” 5,640,705 issued Jun. 17, 1997;U.S. Pat. No. 6,171,451 entitled “Method and apparatus for producingcomplex carbon molecules” issued Jan. 9, 2001; U.S. Pat. Nos. 5,510,098,5,316,636, 5,494,558 and 5,395,496, which use various processes tovaporize carbon rods, producing carbon atoms that recombine intofullerenes; U.S. Pat. No. 5,951,832, “Ultrafine particle enclosingfullerene and production method thereof” issued Sep. 14, 1999, whereinatomic or crystalline species are driven into nanostructure structuresusing an energetic electron beam; and U.S. Pat. No. 5,965,267 entitled“Method for producing encapsulated nanoparticles and carbon nanotubesusing catalytic disproportionation of carbon monoxide and thenanoencapsulates and nanotubes formed thereby” issued Oct. 12, 1999,which are incorporated by reference herein in their entirety.

Furthermore, the shape of all C-60 structures is not necessarilyspherical. Football and cigar shaped structures have been reported, andvery long capped tubes (“bucky tubes”, or carbon nanotubes) have beenproduced. Nanotubes generally comprise a network of hexagonal graphiterolled up onto itself to form a hollow tube-like structure. Thesenanotubes have been made with diameters as small as roughly one (1)nanometer. The length-to-width aspect ratio of nanotubes can be madeextremely high, with lengths on the order of a millimeter or more (1E06nm) compared to diameters on the order of a few nm. Single-walled carbonnanotubes (SWNTs) are produced by any one of several methods, including(i) carbon arcing to vaporize a metal-impregnated carbon electrode; (ii)laser ablation of a heated target; and (iii) catalytic chemical vapordeposition (CCVD), the latter comprising a low temperature techniquemore suited for large scale production of nanotubes. See, for example,U.S. Pat. No. 5,916,642 entitled “Method Of encapsulating a material ina carbon nanotube” issued Jun. 29, 1999, incorporated herein byreference in its entirety.

Another deposition technique for either individual or multiplemulti-walled carbon nanotubes is based on electron beam lithography.Carbon nanotubes are deposited from the solution phase onto a substrate(such as that of the aforementioned MIT microchip drug delivery device)through lithographically determined openings in an electron beamphotoresist layer. The openings may be in size from a few micronsupwards. See Yang, Xiaoyu, “Carbon nanotubes: Synthesis, Applications,and some new aspects”, Thin Films and Nanosynthesis Laboratory,Department of Mechanical and Aerospace Engineering, SUNY at Buffalo,Fall 1999, incorporated herein by reference in its entirety.

It has further been found that selective dissolution of portions of thenanotube (i.e., the so-called “end caps”) may be accomplished throughexposure of the nanotubes to certain oxidizing substances such as acids.See, for example, U.S. Pat. No. 6,090,363, entitled “Method of openingand filling carbon nanotubes” issued Jul. 18, 2000, incorporated hereinby reference. Selective dissolution techniques may be used to preparenanotubes for filling after formation of the tubes, or conceivably beused to release molecules or atoms contained within the nanotube invivo, either before or after release of the nanotubes by the probe intothe intestine.

In an exemplary embodiment of FIG. 20, at least a portion of thenanostructures 2001 (in solution) are released from the container 2004of the probe 2000 generally in contact with the interior wall (e.g.,villi) of the subject's intestine in the localized region of thediseased tissue or tumor. Due to their small size (typically less than200 nm), at least a portion of the nanostructures are drawn into theepithelium 2007 by passive diffusion across the epithelial cellmembranes or other uptake mechanisms, or otherwise remain depositedamong the villi or other structures of the epithelium, and therebydelivering the desired therapeutic dose to the target tissue.

In a second embodiment, one or more complexes comprising a radionuclidemicroparticle coupled to at least one carrier, the carrier being capableof enabling the complex to be transported to the desired tissue orsystem via the epithelium of the intestine. Complex formation andcarrier coupling as used herein are set forth in detail in U.S. Pat. No.6,159,502 entitled “Oral Delivery Systems for Microparticles” issuedDec. 12, 2000, and incorporated herein by reference. Natural mucosalbinding proteins may be employed to target various protein molecules tothe gastrointestinal mucosa and induce their uptake. These bindingproteins may include, for example, any number of lectins, bacterialadhesions, or viral adhesions.

In yet another embodiment of the invention, the pre-existing mechanismfor the natural uptake of Vitamin B1/(e.g., C₆₃H₈₈CoN₁₄O₁₄P; C₃H₆O;20H₂O) is used as the basis for an internalization methodology 2100.First, the nanostructure is bound to the B12 molecule (step 2102). Theprobe is then loaded with the B12 molecules (with nanostructures) perstep 2104, and administered per step 2106. The probe deploys theB12/nanostructures in the small intestine (step 2108). During uptake,Vitamin B₁₂ initially binds to intrinsic factor (IF) in the smallintestine per step 2110. The Vitamin B₁₂-IF complex then proceeds downat least a portion of the small intestine, and binds to an IF receptor(step 2112) located on the surface of the ileal epithelium. The entireVitamin B₁₂-IF-receptor complex is then internalized byreceptor-mediated endocytosis or similar mechanism (step 2114).Accordingly, by attaching the nanostructure (e.g., fullerene) 2040 tothe B12 complex as illustrated in FIG. 21, the radioisotope 2050 presentcan “piggy back” to achieve internalization. Such methods of B₁₂ uptakeare well known to those of ordinary skill in the art, and accordinglyare not described further herein. In one variant of the presentembodiment, the designated radionuclide held within the nanostructurecavity is chosen to have a comparatively short halflife so as tomitigate unwanted exposure to non-diseased tissue after internalization.

In yet another embodiment (not shown), Guanylyl cyclase C (GC-C) is usedto receive the radionuclide. Guanylyl cyclase C (GC-C) is atransmembrane receptor molecule expressed primarily in the intestine.GC-C is expressed in the crypt and villus epithelium of the small andlarge intestine, consistent with normal electrolyte homeostasis.

It will be recognized that while the foregoing discussion is cast interms of the preparation and delivery of radionuclides and theirassociated ionizing radiation to selected tissues within the body, suchmechanisms may as appropriate be utilized with equal success for in vivodelivery of pharmaceuticals or other agents, including for examplechemical compounds, intestinal lubricants, ligands, and gene therapyagents. As is well known, nucleic acids (e.g., DNA, RNA) can beintroduced into the stem cells of the intestinal epithelium using anynumber of methods including transformation, transfection andtransduction. For example, see U.S. Pat. No. 5,821,235 entitled “Genetherapy using the intestine” issued Oct. 13, 1998, incorporated byreference herein, which describes various gene therapies relating to theintestinal tract of a living subject. Where applicable, such genetherapies may be directly delivered by the probe of the presentinvention, when configured as described above.

The present invention may also be used to aid in suppressing auto-immunesystem reactions related to the gastrointestinal tract. Many diseasesassociated with the human gastrointestinal tract (such as Crohn'sdisease) result at least in part from an aberrant immune system responsewithin the subject, the intervention of which may be accomplishedthrough selected delivery of agents targeted for such reactions.

Additionally, it will be realized that mixing of reagents within theprobe (or any “trailer” probe as subsequently discussed herein) may beaccomplished in vivo by the aforementioned methods; e.g., by providingtwo or more chambers which communicate with one another and which areseparated by a rupturable diaphragm or other controllable aperture;under control of the operator (and/or upon the occurrence of apredetermined event), the diaphragm is ruptured or other apertureopened, such as by stored gas pressure, and the reagents in the chambersmixed together. The reagents are subsequently released into theintestinal volume using methods described herein, or alternatively beretained within the probe (or trailer probe), such as in the case of anexothermic reaction where it is desired to produce heat within theintestinal tract, or produce inert or non-toxic gas within the probe togenerate pressure for expulsion of ligands, or other functions.

In another exemplary embodiment of the invention (FIG. 22 a), one ormore specially selected “polymerized” molecules 2202 are disposed withinthe cavity 2204 of the nanostructure 2206 such that the polymerizedmolecule(s) is/are captured therein. The polymerized molecule(s) 2202may comprise, for example, a grouping of ligands targeted for specificreceptor molecules within the intestinal epithelium, or a ligand 2210with a co-associated “retainer” molecule 2212 (FIG. 22 b).

Upon introduction of the nanostructure(s) in vivo, the polymerizedmolecule(s) 2202 are depolymerized or otherwise separated from oneanother, thereby allowing selected components 2208 of the molecule(s)2202 to be extracted or released from the nanostructure 2206 asillustrated in FIG. 22 c. These released components 2208 are thendiffused into, received by complementary receptors 2209, or otherwiseabsorbed by the targeted tissue in the subject. Alternatively, asillustrated in FIG. 22 d, a ligand 2220 is disposed externally to thefullerene cage 2206, thereby allowing bonding to a receptor site 2209with the fully polymerized molecule 2202 intact. In one variant, theligand 2220 with retainer and fullerene attached is received at thereceptor site 2209; the fullerene cage acting to protect the retainermolecule within until internalization of the latter. In another variant,the polymerized ligand and associated fullerene/retainer molecule issufficiently mechanically unstable that the ligand/retainer is “torn”from the fullerene by scission or breaking of the carbon-carbon bonds ofthe fullerene, thereby allowing the ligand (and retainer) to remaindisposed on the receptor.

In yet another exemplary embodiment of the invention, “nanotubes” areformed which contain one or more “payload” pharmaceutical or othermolecules for delivery to the subject. As illustrated in FIG. 22 e, theactive portion 2277 of the ligand 2270 is disposed in a free end 2274 ofthe nanotube 2271, such that the ligand may be readily received by thetargeted receptor on the tumor cells, the payload molecule 2275 beingprotected by the nanotube structure. In yet another variant, thenanotubes are disposed in an array, ligand-side out, such that theligands may be readily extracted from the nanotubes upon reception bythe targeted receptors.

As will be recognized by those of ordinary skill, numerous differentcombinations of nanostructure, retainer molecules, and ligands may beused consistent with the present invention in order to achieve thedesired objectives of delivery of the agent to the desired cells of thesubject via the intestinal tract thereof.

Apparatus and Method for Tissue Biopsy

Referring now to FIGS. 23 a-23 d, an improved apparatus and method forobtaining a biopsy of the intestinal wall of the subject are describedin detail. As shown in FIG. 23 a, one exemplary embodiment of theapparatus comprises a smart probe 2302 of the type previously describedherein, further including a sample mechanism having a plurality ofselectively controlled apertures 2304, a shutter mechanism 2306 withrespective shutters 2307, and associated reservoirs 2308 disposedgenerally in the outer region 2310 of the probe 2302. Upon the probereaching the desired location within the subject's intestine, theshutters 2307 are selectively shut rapidly under spring force, therebysevering tissue present within the apertures and disposing the tissueinto the reservoirs 2308. Intestinal tissue or epithelium protrudingthrough the apertures due to, inter alia, surface tension and/orintestinal contractions, is excised by closing the aperture shutters asillustrated in FIG. 23 b. The excised tissue 2314 is retained within thereservoirs 2308 until the probe 2302 is expelled from the subject, atwhich point the excised biopsy tissue may be examined using any numberof well known analytical techniques.

Referring again to FIG. 23 a, the shutter mechanism 2306 comprises aspring-loaded annular ram 2327 which is generally cylindrical in shapeand which slides within a complementary bore 2329 formed within thehousing 2303 of the probe 2302. The bore and ram are sized such topermit free longitudinal travel of the ram 2327 in the bore withoutcocking or pitching thereof. A return spring 2330 is disposed at therear-most portion 2332 of the probe housing 2303, the forward end 2334of the spring contacting the rear face 2336 of the ram 2327 and urgingthe latter forward (and shutters 2307 attached thereto) with sufficientforce to sever the tissue protruding within the apertures 2304.

The shutter mechanism 2306 of the present embodiment further includes aselectively releasable retaining mechanism 2340. The retaining mechanism2340 comprises generally a pair of articulated, retractable detents 2342disposed relative to the ram 2327 such that when the ram is in its fullyretracted position with the restoring spring 2330 nearly or fullycompressed, the tabs 2345 of the detents 2342 engage the leading edges2346 of the ram, such that the ram is retained in the retractedposition. The pivot points 2343 of the detents are disposed, and thedetents shaped, such that the detents will “lock” in position and retainthe ram retracted with no force on the free ends 2349 of the detents.This is how the probe 2302 is configured upon administration within thesubject. At least the free ends 2349 of the detents 2342 are metallic inconstruction (ferrous) such that they are attracted by a simple magneticcore 2350. The magnetic core 2350 comprises a substantially cylindricalferromagnetic element with magnetic dipoles substantially aligned suchthat a polar magnetic (B) field is generated by the magnet 2350. A fieldcoil 2360 is disposed in annular proximity to the core 2350 andelectrically connected to a source of electrical potential (such as theprobe battery, or external power supply coupled to the probe aspreviously described) and microcontroller 520 such that upon assertionof a command signal from the microcontroller (such as may be generatedby receipt of an RF, inductive, capacitive, or ultrasonic control signalgenerated externally to the subject), the electrical potentialdifference induces current to flow within the field coil 2360, therebygenerating a secondary magnetic field in proximity to the coil. As iswell understood in the electromagnetic sciences, the interaction betweenthis secondary magnetic field and that generated by the core 2350results in a displacement force between the core 2350 and coil 2360.Since the field coil is fixed to the probe housing in the illustratedembodiment, the core 2350 is longitudinally displaced in a rearwarddirection 2362, thereby reducing the distance of the core to the freeends 2349 of the detents. As the aft end 2366 of the core 2350 closelyapproaches the free ends 2349, the magnetic coupling of the ferrous freeends and the magnet core increases, thereby generating an increasedattractive force tending to draw the free ends 2349 to the magnetic core2350. Due to the relative disparity in torque around the pivot points,the detents 2342 rotate around their respective pivots, thereby allowingthe tabs 2345 to disengage the ram sufficiently that the latter isreleased and rapidly forced forward by the spring thereby “snappingshut.” The shutters 2307 are each attached to the ram 2327 of theshutter mechanism 2306, and fashioned from metal or other non-brittlematerial capable of being sharpened to a tapered edge 2399. The leadingedges 2399 of the shutters 2307 are, in the illustrated embodiment,tapered (sharpened) so as to cleanly sever the biopsy tissue uponrepositioning of the shutters to their closed position by theram/spring.

A bias spring 2388 is disposed between the central support and pivotassembly 2380, the latter being attached transversely via supportelements 2377 to the interior walls of the probe housing 2303 as shownin FIG. 23 c, thereby tending to bias the core 2350 forward from thefixed support 2380. This prevents inadvertent movement of the magneticcore (such as due to gravity) into proximity to the free ends 2349thereby inadvertently triggering the shutter mechanism 2306. The biasspring size and constant is selected so as to just prevent translationof the core 2350, but not larger, thereby minimizing the electricalcurrent required in the field coil 2360 to overcome the spring andtranslate the core assembly 2350 when desired.

Further bias springs 2390 are attached to the detents 2342 toward thefree ends 2349 thereof. These springs 2390 have a low spring constant,thereby just tending to keep the detents 2342 biased outward, therebyensuring continued engagement of the tabs 2345 to the leading edges ofthe ram retainer ring 2346.

The apertures 2304 of the illustrated embodiment are advantageouslysized and shaped such that, at a maximum, only the desired amount oftissue will protrude into the reservoirs 2308 through their respectiveapertures, thereby limiting the amount of tissue that may be obtained ina single biopsy. Such limitation is desirable to preclude undesirabletrauma to the intestinal wall, such as significant laceration orperforation. The elongated shape of the apertures 2304 (FIG. 23 b) isfurther oriented such that the longer dimension 2322 of each aperture isperpendicular to the longitudinal axis 2324 of the probe 2302, andconformal to the outer circumference of the probe. In this fashion, theintestinal tissue strewn across each aperture when its respectiveshutter 2307 is retracted by the shutter mechanism 2306 “sags” or drapeswithin the apertures, especially in the central portions 2325 thereof.The depth 2321 of the reservoir is also selected so as to limit thepenetration of the tissue into the probe, thereby further safeguardingthe intestinal wall.

The foregoing biopsy mechanism arrangement has the advantage of storingpotential energy for severance of the intestinal tissue in the form ofthe compressed spring, thereby obviating the need for significantelectrical energy stores within the probe to operate the biopsymechanism. It will be recognized, however, that other motive forces orsources of potential energy may be utilized consistent with theinvention. For example, the ram 2327 may be motivated by the controlledrelease of compressed gas behind the ram, such gas being stored within achamber in the probe (or a “trailer” probe). Many other suchalternatives are available, all such alternatives being within thepossession of those of ordinary skill in the mechanical arts.

In another embodiment (not shown), the normally closed shutters 2307 areselectively opened upon the probe reaching the desired location withinthe subject's intestine, thereby exposing the reservoirs 2308 to theenvironment external to the probe. An electromagnetic solenoid of thegeneral type previously described herein with respect to the radiationshield retraction mechanism (FIG. 18) is used to overcome therestorative force of a spring 2330 during shutter retraction; uponcollapse of the magnetic field of the solenoid (induced by a signal fromthe microcontroller or other control scheme which interrupts currentflow to the solenoid field coil), the magnetic core 2350 and attachedshutters 2307 translate forward along the longitudinal axis of the probeunder spring force, thereby severing the intestinal tissue residentwithin the apertures 2304. While obviating the detents 2342, thisapproach requires significantly greater electrical power to overcome therestorative force of the severance spring 2330 during shutterretraction, and hold the shutter open until tissue enters the apertures.

In yet another embodiment (FIG. 24 a), the probe 2400 includes one ormore selectively controllable pop-up “scoops” 2402 which are disposed onor near the surface of the probe; when activated, the scoop(s) 2402collect tissue cells as the probe traverses the intestine, and depositthe collected tissue within reservoirs 2403 disposed adjacent to thescoop inlets. The probe is then retrieved after secretion for biopsytissue analysis.

As illustrated in FIG. 24 a, the scoop is mechanically coupled to aneccentric element 2404 which is disposed within the outer housing 2402of the probe. The eccentric 2404 interacts with a cam surface 2408formed on the lower surfaces of the scoop 2402 such that when theeccentric is translated along the longitudinal axis 2409 of the probe2400, the scoop 2402 is extended (i.e., “pops up”) above the surface ofthe outer housing 2402. Conversely, when the eccentric 2404 istranslated in the opposite direction, the scoop is retracted to conformgenerally with the surface of the housing 2402, as illustrated in FIG.24 b. A restorative bias element (e.g., spring) 2411 is used to returnthe scoop 2402 to a nominal (retracted) position when the eccentric 2404no longer bears on the cam surface 2408. Approaches other than a springmay be substituted with equal success, however.

The eccentric 2404 of the present embodiment is fabricated from aferromagnetic material, and further includes a cylindrical end portion2415 which is disposed substantially within a conductive coil element2417. Electrical current applied to the coil element 2417 generates amagnetic (B) field local to the coil, thereby interacting with themagnetic field of the end portion 2415 to translate the eccentric, aspreviously described herein with respect to other aspects of theinvention. A restoring spring 2418 is disposed against another portion2419 of the eccentric 2404 as well as a bulkhead 2420 or other structurewithin the probe housing such that in the normal (non-energized)position of the eccentric 2404, the scoop is retracted as in FIG. 24 b,due to the restoring force exerted by the spring. Hence, upon battery(or external power source) failure or degradation, the scoop 2402 failsshut, thereby allowing for unimpeded passage of the probe 2400 throughthe intestine of the subject.

Additionally, it is noted that the cam surface 2408 and eccentric 2404may be configured such that a significant disparity in mechanicalleverage exists between force applied at the leading edges 2421 of thescoops and the eccentric 2404. In this fashion, the eccentric 2404 maymore readily overcome any normal or other forces on the scoops 2402applied by the intestinal wall, etc. which would tend to resist scoopopening or closure. The cam surfaces and bottom of the scoop bucket 2403are contoured to allow the scoop 2402 to be extended with minimalfriction between the eccentric and the scoop. Accordingly, inconjunction with the aforementioned bias springs 2411, the scoops 2402can be relied upon to both open and shut under the anticipated operatingconditions.

The scoops 2402 of the present embodiment are shaped with generallyrounded contours so as to mitigate the possibility of laceration or“catching” on the intestinal epithelium, as shown in FIG. 24 b. It willbe recognized, however, that under certain circumstances, it may bedesirable to have the scoops 2402 shaped so as to increase thelikelihood of such “catching”, so as to ensure the capture of asufficient biopsy sample. Accordingly, while the present embodimentshows a substantially cylindrical scoop 2402, the present inventioncontemplates scoops of a variety of different configurations.

The scoop 2402 of the present embodiment is also sized, and the maximumelevation above the outer surface of the probe selected, such that onlyincidental interaction between the scoop 2402 and the epithelium occurs,thereby mitigating the chances of the probe “sticking” in a givenlocation within the intestine. Alternatively, however, the scoop(s) maybe configured and used to intentionally “stick” the probe at a givenlocation within the intestinal tract, thereby permitting more extendedtherapy to that region of tissue, such as in the case where extendedradioisotope therapy is required. Specifically, the scoop(s) 2402 (orother projections without the capability to collect tissue biopsy, ifdesired) may be sized and positioned upon extension such that they aredisposed a significant height above the surface of the probe, therebycontacting and slightly distending the intestine wall in the regionimmediately surrounding each scoop. This distension and friction on theprobe scoops substantially slows and may even temporarily stop themovement of the probe within the intestine.

The embodiment of FIGS. 24 a-b has the additional benefit of samplingrepeatability; i.e., the scoop 2402 may be selectively raised andlowered repeatedly (assuming sufficient battery or other electricalpower), thereby allowing for sampling of tissue at different portions ofthe intestine. In the embodiment of FIG. 24 a, subsequent samplescollected in the scoop bucket 2403 will be disposed generally in alayered fashion, irrespective of probe orientation. Such layers orstrata are identifiable by those analyzing the biopsy sample afterexpulsion.

Note also that while the embodiment of FIGS. 24 a and 24 b illustrate ascoop 2402 which translates in generally a radial direction as measuredfrom the longitudinal axis of the probe, other approaches may beemployed, such as having the scoop 2402 substantially hinged at one end,such that it rotates around the hinge axis.

It will be recognized that in addition to the embodiments described indetail herein, many different mechanisms may be used to effectuatetissue sampling or biopsy within the intestine of the subject using anautonomous probe, such mechanisms being known to or readily fashioned bythose of ordinary skill. Accordingly, the embodiments disclosed hereinare considered merely exemplary in nature.

Apparatus and Method for Treating Constrictions

Referring now to FIG. 25 a, an improved apparatus and method fortreating constrictions, obstructions (or adhesions occurring between theinterior surfaces of the intestine wall) of the intestinal tract aredescribed in detail. In the exemplary embodiment of FIG. 25 a, theapparatus 2500 comprises a two-part smart probe having a front sectionwith reduced radius, and being equipped with a deformable element 2506which expands the effective radius of the probe in at least a portion2508 of its cross-section, thereby simultaneously expanding thesurrounding intestinal tissue. The variant of FIG. 25 a includes apressurized gas reservoir 2510 in the form of a follow-on probe (or“trailer”) which acts as a source of potential energy for the deformableelement 2506 upon activation, thereby minimizing the electrical powerrequirements of the device. In the present embodiment, the deformableelement 2506 comprises an elastomeric “bladder” akin to those used inwell known arterial catheterization/angioplasty instruments, such asthat described in U.S. Pat. No. 5,100,381 entitled “Angioplastycatheter” and issued Mar. 31, 1992, incorporated by reference herein.The probe 2500 comprises two major housing elements 2512, 2514 which arecoupled by a flexible, annular coupler or umbilical 2516. The annularcoupler is rigid enough to withstand pressurization by the gas reservoir2510 of the trailer and preclude collapse of the annulus 2517 duringbending, yet flexible enough to allow movement of the probe 2500 as awhole through the tortuous intestine. Myriad polymeric materials havingsufficient flexibility and strength (including, for examplepolyethylene) may be used, although any material presenting the desiredproperties may be substituted.

The trailer housing element 2514 substantially comprises a pressurizedgas reservoir 2510 containing a quantity of pressurized inert gas (suchas N₂). The annular coupler 2516 includes an annulus 2517 and internalaperture 2518 with associated diaphragm 2520 disposed therein, such thatprior to release of the pressurized gas, the pressure of the gas in thetrailer 2514 is maintained substantially above atmospheric (orprevailing intestinal tract pressure) by the diaphragm 2520. Theaperture 2518 communicates with the probe housing element 2512 such thatupon rupture or dislocation of the diaphragm 2520, the gas volume of thetrailer is permitted to expand into the deformable element 2506 suchthat the latter expands in a generally radial direction 2522 in responsethereto (see FIGS. 25 b and 25 c). In the present embodiment, thedeformable element 2506 comprises an elastomeric (e.g., natural or latexrubber) balloon adapted to contain the full pressure of the compressedgas stored in the trailer without bursting (at atmospheric pressure oralternatively the lowest pressure anticipated to be encountered withinthe intestine). The forward portion 2525 of the front housing element2512 is rigidly attached to the rear portion 2526 thereof by two supportmembers 2528, thereby forming a cavity 2529 there between. The cavity2529 substantially contains the deformable element 2506 when the latteris in its non-inflated state. The rear housing element 2514 contains theelectronics 2532 (e.g., RF transceiver 2534, controller 2535, powersupply regulation circuit 2536, etc.) and power supply 2537.Alternatively, the forward portion 2525 may contain the probebattery/power supply 2530, electrical potential from which iscommunicated to the other electronics disposed within the rear portionof the rear housing element 2514 via two conductive traces (not shown)disposed on or within respective ones of the support members 2528, andthe umbilical 2516.

Upon pressurization, the deformable element (balloon) 2506 expandsgenerally forward toward the front portion 2525 of the housing element2512 until the rear bulkhead 2540 is encountered by the balloon 2506. Atthis point, the balloon expands more radically outward, increasing theeffective radius 2542 of the front housing element 2512 significantly,as illustrated in FIG. 25 c. Upon contacting the intestinal wall tissue,the balloon continues to expand radically at a slower rate (due to therestorative force applied thereto resulting from the elasticity of theintestinal tissue), thereby exerting force on the underlyingconstrictive element. At equilibration, the balloon 2506 is fullycontacted with the distended intestinal wall, the pressure within theballoon and trailer gas chamber being equal. As is well known, thepressure-volume product PV for a gas remains constant at constanttemperature (Boyle's Law). Hence:P ₁ V ₁ /T ₁ =P ₂ V ₂ /T ₂

Where

p₁=pressure at volume V₁

p₂=pressure at volume V₂

Therefore, if the ratio of the volume of the expanded balloon 2506, gaschamber, and annular volume is five (5) times the volume of the gaschamber V₁, then the ratio of the pressures will be ⅕ or 20% (assumingconstant temperature for both initial and final states). If the ultimatepressure needed to satisfactorily inflate the balloon 2506 is 5 psi,then the same gas chamber must be initially pressurized to roughly 25psi. Total interior surface volume of an exemplary cylindrical chamber2510 of length 20 mm and radius 6.5 mm (I.D.) is approximately 1.4 sq.in., thereby generating a total surface force of about 35 lb. on thechamber walls at 25 psi.

The foregoing calculation is merely exemplary, and the actual pressurerequired may vary based on changes in temperature, use of non-idealgases and non-adiabatic processes, etc. Note that the elasticity andvolume of the balloon, size and volumetric capacity of the trailer, andpressurization of the latter, are all readily calculated using wellknown mathematical modeling techniques, or alternatively may beempirically determined such as though trials using cadaver intestine.Furthermore, during expansion of the compressed gas into the balloon,the temperature (thermal energy content) of the gas will decreaseslightly, thereby effectively “chilling” the balloon 2506, gas chamber,annulus 2516, and adjacent portions of the probe.

Pressurization of the gas chamber 2510 is accomplished in theillustrated embodiment using a pressurization port 2577 disposed on theside of the chamber 2510; the port contains a one-way bladder valve akinto that used in inflatable sports equipment, thereby allowing insertionof a small diameter (e.g., 1.0 mm) inflation probe or needle (not shown)for pressurization of the chamber. It will be recognized, however, thatother approaches may be used.

In the simple case, design leak-off of the system (such as throughutilization of a semi-permeable balloon membrane, or leak-by on thejunction of the balloon and annular coupler) may subsequently be used todeflate the balloon 2506, although other methods such as selectiverupture of a secondary diaphragm (not shown) under electrical currentmay be utilized to relieve pressure when desired.

However, despite the foregoing utility, certain intestinal constrictionsmay not respond to the therapy provided by the probe 2500. Use of theprobe 2500 for treatment of complete obstructions of the intestine maybe contra-indicated. In such circumstances, despite the reducedcross-sectional area of the probe 2500 (as compared to other embodimentsdescribed herein), the probe 2500 may become lodged against theobstruction or constriction. Surgical removal of the probe 2500 wouldthen likely be required. However, such measures may be untenable forcertain subjects (such as those not otherwise requiring invasivesurgery); accordingly, a method of dislodging the probe under suchconditions is needed.

Accordingly, the probe 2500 of the invention may further be configuredwith a pressure sealing element (e.g., ridge or conic section) 2548disposed on the rear portion 2526 of the front housing element 2512,shown in FIG. 25 d with inflatable element 2506 removed. The sealingelement 2548 acts to contact the inner surface of the intestinal wall,thereby forming at least a partial seal there between. To dislodge theprobe, inert gas is administered to the intestinal tract via anendoscopic catheter or tube introduced via the esophagus of the subjectsuch as by intubation (not shown); the inert gas fills the intestine,lightly pressurizing the same (the pressure being controlled so as toavoid any trauma or rupture thereof), and exerts a longitudinal force onthe probe 2500 due to the differential pressure across the sealingelement 2548. The frontal portion 2550 of the front housing element 2512is further shaped in a tapered, elliptical semi-conic section (“bullet”configuration) such that penetration through the constriction isfacilitated. The sealing device may further be equipped with a smallfluid reservoir (not shown) containing a liquid lubricant, the latterbeing displaced from the reservoir and though passages in the frontalportion 2550 upon the application of differential pressure across thesealing element 2548, thereby reducing the coefficient of frictionbetween the probe housing elements and the intestinal wall. The diameterof the rear (trailer) housing element 2514 is also made smaller than thediameter of the sealing element 2548, thereby allowing pressurized inertgas to flow readily around the periphery of the trailer.

As will be readily recognized, the aforementioned configuration affordsseveral advantages, including (i) reduced cross-sectional area of bothfront and trailer probe housing elements 2512, 2514 as compared to asingle probe so equipped; (ii) enhanced pressurized gas (potentialenergy) storage capacity for increased mechanical advantage against theconstricted intestine, and (iii) provision of a sealing element usefulfor facilitating passage of the probe through constrictions.

It will be recognized, however, that a gas generant such as thatpreviously described herein may be substituted for the pressurizednitrogen chamber of the embodiment of FIG. 25. Such gas generant may becontained within a specially constructed variant of the inflatableelement 2506, the latter being adapted to withstand the heat generatedby the gas generant during reaction. Since the gas generant consumes asmaller portion of space within the probe than the pressurized gasreservoir, the dimensions of the probe may be adjusted accordingly, oreven contracted into a single housing element if desired.

In yet another embodiment of the apparatus for treating constrictions,the probe 2500 alternatively comprises a micro-solenoid assembly (notshown) with a cam-like structure such as that described previouslyherein with respect to FIG. 24 which, based on the application ofelectrical current through the coil of the solenoid, permits a portionof the probe to expand (and subsequently contract) under command of theprobe's microcontroller or other external signal. Numerouselectro-mechanical configurations for accomplishing such expansion andcontraction of the probe are available and possessed by those ofordinary skill in the mechanical arts, and accordingly will not bedescribed further herein.

Referring now to FIG. 26, a method of treating constrictions within theintestinal tract of a living subject are disclosed. In one exemplaryembodiment (illustrated in FIG. 26), the method of treating 2600generally comprises first disposing the probe 2500 within the intestineof the subject proximate the constriction (step 2602 and 2603). This maybe accomplished through direct oral administration of the probe 2500, ormore preferably, through endoscopic insertion of the probe using aninsertion/delivery device such as that described previously herein.Endoscopic delivery of the probe is preferred due to the asymmetries ofthe shape of the probe, and the need to orient the probe properly withinthe intestine (i.e., front housing element 2512 first into theintestine). The probe 2500 is next caused to expand in radius orotherwise deform its shape so as to expand at least a portion of theconstriction, (step 2604) as previously described in detail. In oneexemplary variant of the method 2600, the probe is tracked usingconventional X-ray or ultrasonic techniques such that it's proximity tothe constriction can be accurately determined. When properly positioned,the probe is expanded within the constriction as required to at leastpartially relax the constriction. In another variant, the probe 2500 isfurther outfitted with a radio frequency, ultrasonic, or other trackablesignal emitting device, and the probe tracked via emitted radiofrequency, ultrasonic, radiation, or other tracking signals. In yetanother variant, a piezoelectric transducer element disposed on theprobe (described below) is used in conjunction with on-probe or externalsignal processing apparatus to acoustically determine the proximity ofthe probe to the constriction/obstruction through “echo ranging” oralternatively ultrasonic imaging of the constriction. In yet anothervariant, the CCD or MOS visual or IR imaging array previously describedis used to visually determine the proximity of the probe to theconstriction/obstruction.

In a second embodiment, the method of treating intestinal constrictionsaccording to the present invention comprises disposing the probe withinthe intestine of the subject proximate the constriction; and causing theprobe to release one or more agents in the intestine so as to induceexpansion or contraction of at least a portion of the constriction. Forexample, the present invention contemplates the delivery ofpharmacological agents such as mesalamine (e.g., Asacol®) oramytriptaline (e.g., Elavil®) which may tend to induce relaxation of theintestine, although other even more aggressive agents may be substitutedor used in concert with the foregoing.

Alternatively, the probe may be adapted to generate significantelectrical potentials through use of a miniature capacitor ormicroelectronic toroidal core transformer of the type well known in thesurface mount electronics arts, from energy stored in the improvedgraphite composite structural energy storage mechanism describedsubsequently herein, or alternatively via other on-probe storage devicesor off-probe power sources. When applied to the intestinal wall, suchpotentials induce current flow therein, the latter resulting instimulation of the intestinal muscle into a state of temporarycontraction, as is well understood. Properly timed and positioned, suchcontraction around the centrally positioned probe can result in, interalia, temporary relaxation of the intestinal constriction and/or passageof the probe.

As yet another alternative, the probe may be adapted to generatelocalized magnetic fields which, despite the current lack of credibleevidence supporting their efficacy, may in certain contexts be proven tohave therapeutic effect. Generation of such magnetic fields may beaccomplished through the inclusion of a high-density ferromagnet orelectromagnet within the probe, for example. Conductive coils disposedhelically around the electromagnet carry electrical current (generatedby the potential difference created by either on-probe sources, oroff-probe power sources are electromagnetically or inductively coupledto the probe) which aligns the magnetic domains with the ferromagneticmaterial, and enhances the B-field strength in the vicinity of theprobe. Alternatively, a “trailer” probe carrying a larger electromagnetmay be utilized. The probe may then be purposely “stuck” within theintestine using the aforementioned outwardly projecting scoops or othercomponent, thereby allowing for prolonged exposure of a selected regionof tissue to the magnetic field generated by the probe.

“Smart” Probe Housing

Referring now to FIGS. 27 a-c, an improved autonomous probe having a“smart” housing and electronics configuration is disclosed. As used inthe present context, the term “smart housing” refers generally to thescience of structural electronics, largely pioneered by D. D. L. Chung,et al, of University of Buffalo, N.Y., although the invention is notlimited to the methods developed by Dr. Chung or in fact any otherspecific technique. One of the salient benefits of such structuralelectronics is the significant savings in space provided by integratingotherwise discrete components or functionalities within a single device.Such benefit is particularly applicable in the context of the presentinvention, in that the size of the device which can successfully passthrough the intestinal tract of a living subject is limited, andaccordingly space it at a premium within such devices. Hence, the sameprobe incorporating structural electronics may be made smaller than itscounterpart not so equipped, or alternatively more capacity andfunctionality can be included within a probe otherwise of the same size.

As illustrated in FIG. 27 a, the probe 2700 comprises a structuralelectronic housing 2702 formed at least in part from multi-layer carbonfiber composite material which is encased in an insulating coating 2703.The carbon fiber composite material 2710 comprises a plurality ofsubstantially concentric sheets 2712 of polymeric (e.g., epoxy resin)matrix in which a plurality of micro-diameter “electrically conductive”graphite carbon fibers 2714 have been selectively disposed (FIG. 27 b)in a predetermined, non-colinear but generally planar orientation. Theterm “electrically conductive” is used with respect to the instantdiscussion to refer to any level of conductivity greater than that of asemiconductor, since in most cases, the graphite fibers are not nearlyas electrically conductive as comparable traditional copper oralloy-based conductors.

In order to make the best possible of use of available space within theprobe, and/or reduce the weight thereof via reduced batteryrequirements, the sheets 2712 of the housing 2702 are disposed centrallywithin the midsection 2711 of the housing 2702 such that two concentriccylinders are formed. It will be recognized that while the embodiment ofFIG. 27 a illustrates two concentric cylinders of matrix material whichterminate at the juncture 2715 of the ellipsoid/hemispherical endportions 2713 of the housing 2702, the sheets 2712, with properfabrication technique, may comprises a greater fraction of the housingelement 2702, thereby affording greater energy storage capacity. Theentire housing 2702 may conceivably be fabricated using the multi-sheetcomposite construction of the present invention; however, thecylindrical section disposed in the midsection of the probe 2700 of FIG.27 a is chosen for ease of construction, as well as ease of analysis.

As shown in FIG. 27 c, the matrix sheets 2712 are separated by a highdielectric constant material (e.g., insulator) 2717 comprising astrontium titanate/Microlam® composite, having a dielectric constant ofabout 300. It will be recognized, however, that other dielectricmaterials such as impregnated kraft paper, ceramic, or any other one ofa plethora of suitable insulating materials well known in the electricalarts, may be used, consistent with the power requirements of the probeas discussed below. The high dielectric constant of the strontiumtitanate/Microlam composite facilitates the storage of greater energywithin the capacitor, as is desirable.

As is now known, such polymer matrices, when so formed, are electricallyconductive in the plane 2720 of the sheets 2712, and also exhibitsemiconductive properties in the transverse dimension 2722 (i.e., normalto the plane 2720 of the sheet 2712). See D. D. L. Chung and S. Wang,“Carbon Fiber Polymer-Matrix Composite as a Semiconductor”; 5th AnnualInternational Symposium on Smart Structures and Materials, TheInternational Society for Optical Engineering, San Diego, 1998. Althoughnot verified, apparent negative electrical resistance in the transverseof similar composites was also observed. See also Shoukai Wang and D. D.L. Chung, “Apparent Negative Electrical Resistance in Carbon FiberComposites,” Composites, Part B, Vol. 30, 1999, p. 579-590. Furthermore,dependent on the temperature and pressure applied to the matrices duringformation, the material and electrical properties of the resultingsheets 2712 may be substantially altered (Chung, et al.).

Accordingly, as the sheets 2712 are transverse semiconductors andco-planar conductors, the sheets with interposed dielectric act as alarge parallel-plate capacitor (Chung; “UB research”, University ofBuffalo, Vol. 8, No. 1, Spring 1998) capable of storing quantities ofelectrical charge in a fashion akin to a conventional capacitor. Hence,the housing 2702 of the present embodiment of the invention acts as anenergy storage device, thereby partially obviating (or even totallyobviating in certain applications) the need for other on-probe energystorage.

As is well known in the electrical arts, the capacitance per unit lengthof infinite concentric conductive cylinders is given by the followingrelationship:C/L=2π∈/ln(b/a)Where:

C=capacitance

L=length

∈=permitivity of interposed dielectric (∈₀×dielectric constant)

b=radius of outer conductive sheet

a=radius of inner conductive sheet

The concentric cylinders of the present embodiment are by no meansinfinite, and hence there is error when applying the equation above tocalculate the capacitance (and ultimately energy storage capacity) ofthe housing 2702. However, for purposes of illustration and simplicity,the concentric cylinders of the embodiment of FIG. 27 a are consideredinfinite.

Based on a nominal outside sheet radius of 6.5 mm and an inside sheetradius of 5.75 mm (0.75 mm thickness of the composite strontiumtitanate/Microlam dielectric), and dielectric constant of 300, thecapacitance obtained per unit length is roughly 0.136 E-06 Farad/meter.For a 25 mm long center section as in the exemplary embodiment, thecapacitance is therefore roughly 3.4 nF or 0.0034 μF. The dielectricstrength of Microlam is given to be greater than 700 V/mil, where onemil=0.0254 mm. Hence, for a 0.5 mm (6.5 mm-5.75 mm-0.25 mm strontiumtitanate) thick Microlam insulator sheet, the withstand voltage is onthe order of 700 V/mil×1/0.0254 mil/mm×0.5 mm=13,780 V. Hence, a voltageof about 13,700 V can be readily sustained by the aforementionedinsulator sheet without dielectric breakdown. The capacitor(specifically, the housing charging terminals) is placed across acharger (not shown) which generates this voltage prior to administrationof the device in vivo, thereby charging the capacitor, at which pointthe probe may be removed from the charger. The probe charging terminals2799 in the illustrated embodiment are disposed internal to the probesuch that the probe must be disassembled in order to charge the housingcapacitor; hence, an inherent patient safety feature is present, sincethe probe housing structural capacitor can not “short” and dischargeacross the subject's intestine or other tissue while in vivo, since (i)it is covered with a dielectric coating, and (ii) the terminals arecontained entirely within the interior volume of the probe. It will berecognized, however, that other safety measures may be employedconsistent with the invention.

The dielectric coating placed on the outer surface of the probe may beany commercially available polymer such as the aforementioned Tefzel orTeflon, although other materials may be used.

The charge Q stored in the structural capacitor is given by:Q=CVTherefore, for the capacitor of the present embodiment, the storedcharge (at 13,700 V)=13,700 V×0.0034E-06 F=46.6 μC. Now assume a 50 ms,100 μA (constant) current pulse drawn from the capacitor. This means acharge loss of ΔQ, where:ΔQ=IΔt=100E-06×50E-03=5.0 μCThe charge remaining after the pulse is 46.6 μC-5.0 μC=41.6 μC. Thecapacitor voltage is thenV=Q/C=41.6 μC/0.0034E-06F=12,235 VIf the current drawn from the capacitor is not constant, then

$\begin{matrix}{{V(t)} = {\frac{Q(t)}{C} = \frac{Q_{0} - {\int_{0}^{t}{{i(t)}\ {\mathbb{d}t}}}}{C}}} \\{= \frac{{CV}_{0} - {\int_{0}^{t}{{i(t)}\ {\mathbb{d}t}}}}{C}} \\{= {V_{0} - {\frac{1}{0}{\int_{0}^{t}{{i(t)}\ {\mathbb{d}t}}}}}}\end{matrix}$where V₀ is the initial voltage on the capacitor. As is well, known, theenergy stored in a capacitor is given by:E=CV ²/2Hence, the maximum energy stored in the “structural” capacitor of theinvention is roughly [3.4E-09×(13,700 V)²]/2=0.319 Joules or 319 mJ,which can be discharged almost instantaneously if required. In terms ofpower, this relates to about 5 mW for about one minute, 0.5 mW for tenminutes, or 0.0866 mW for one hour. Accordingly, the structuralcapacitor of the invention can supply substantial power in support ofprobe operation, especially certain “high draw” transients such asablation laser diode operation, micro-solenoid operation, and the like.

Comparatively, a typical miniature battery NiMH or Lithium battery ofthe type described previously herein, having a capacity of 10 mA-H at3.0 V nominal, will produce power according to:P=IVHence, when considering operation over a one-hour period (i.e.,depletion of the battery's chemical enemy over one hour at a draw rateof 10 mA), the derived power equals 10E-03A×3.0 V=3E-02 V-A=0.03 W or0.03 J/s. Integrating over the one-hour time period (3600 seconds), thebattery supplies a maximum of 0.03 J/s×3600 sec.=108 J of energy.However, such energy can only be drawn out of the battery at acomparatively slow rate based on, inter alia, internal resistance andthermal restrictions associated with the battery, and furthermore, thevoltage characteristic at battery end-of-life (EOL) degrades, such thatthe battery is not practically usable for its entire stored energy(i.e., not all 108 J can be drawn from the battery by the probe,especially since the probe electronics will only operate down to apredetermined voltage level; roughly 1.0-2.7 V depending on the type ofIC components used). Total power consumption of the probe device (basedon DSP operation, CCD, ADC, and other related components/processing) ison the order of between 5-500 mw peak, depending on status (i.e.,whether processor “sleep mode” is invoked, status of the whitelight/laser LEDs if so equipped, etc.)

It will be recognized that the structural capacitor of the invention maybe enhanced for greater energy storage capacity through (i) increasingthe size of the capacitor (i.e., effective length L, which correlates toincreased “parallel” plate area; (ii) the use of a material with higherdielectric constant and/or higher dielectric strength; (iii) use ofmultiple layers of dielectric and additional plates (i.e., formation ofa “double layer” capacitor; and/or (iv) the use of other on-probecapacitors. With respect to Item (iv), it will be recognized that atrailer probe as described below with respect to FIG. 34 may beconfigured as an additional “parallel plate” capacitor for this purpose.

Energy is transferred out of the structural capacitor using a pluralityof conductive traces (not shown) disposed on the interior surfaces ofthe probe housing which are electrically connected to the terminals 2799of the structural capacitor. The traces are deposited on the interiorsurface in sufficient thickness (on the order of 0.003 in) so as toendure the maximum transient (e.g., laser ablation) current withoutsignificant ohmic heating, yet maintain a small physical profile. Otherattendant circuitry well known in the electronic arts (including forexample a zener diode for maintaining a constant voltage across loadsusing the structural capacitor, load resistor, and transistor-basedswitch for transferring power supply from the battery, etc. to thestructural capacitor) are disposed within the probe housing, such as onone of the miniature PCBAs 510 referenced herein, or alternatively in anapplication specific integrated circuit (ASIC) of the type previouslydescribed.

Referring now to FIG. 27 d, one exemplary embodiment of the method offabricating the structural capacitor of the invention is described. Asshown in FIG. 27 d, the method 2760 comprises first providing a form oranvil (e.g., cylindrical shape) over which the capacitor will be formed(step 2761). The first layer of matrix material (e.g., epoxy) for theinner sheet 2712 is then deposited on the anvil in step 2762. The carbonfibers are then spun or sprayed onto the first matrix layer in step2763. The second layer of matrix material is then deposited over thecarbon fiber layer in step 2764. Next, the strontium titanate layer isdeposited on the second matrix layer per step 2765. The Microlam layeris then applied atop the strontium titanate to the desired thickness perstep 2766. Subsequent layers of matrix, carbon fiber, and matrix aresubsequently applied to the capacitor sequentially per steps 2767through 2769. The two electrical terminals 2799 are also disposed inelectrical contact with the carbon fibers of their respective sheet 2712during deposition of the fibers per steps 2763 and 2768. Lastly, theouter insulative coating is applied to (e.g., sprayed onto) the finishedcapacitor after curing of the epoxy matrices per step 2770, therebyproviding enhanced dielectric strength. Note that multiple matrixlayers/sheets may be built up using the foregoing process; hence, threeor more layer capacitors may be formed if desired. Additionally, thecomposite strontium titanate/Microlam dielectric layer(s) may be formedoff of the anvil, and then deposited as a single layer atop the firstsheet 2712. Other such variations are also possible.

Referring now to FIG. 28, a second embodiment of the autonomous probewith “smart” housing is described. In this second embodiment, portionsof the probe housing are fabricated from aforementioned multi-layerlaminated semiconducting/conducting carbon fiber polymer matrix sheets2712, the latter integrating the functionality of one or more otherwisediscrete electronic or opto-electronic semiconductor components withinthe housing itself, thereby obviating the need for the separatecomponents which consume much additional space within the probe.

As illustrated in FIG. 28, the probe 2800 comprises a carbon fibercomposite matrix housing 2802 having at least one active semiconductiveregion 2804 formed therein. While the following discussion is cast interms of an exemplary semiconductor device adapted to emit infraredradiation with band gap energy on the order of 0.01 eV to 0.1 eV (see D.D. L. Chung and S. Wang, previously cited herein), it will be recognizedthat semiconductor devices tuned to other band gap energy values may befabricated and used consistent with the invention. For example, a devicehaving bandgap energy in the range of approximately 1.7 eV and beingused to generate the desired wavelength of light (roughly 700 nm) forautofluorescence analysis or ablation may be substituted or used inconcert. Other band gap energies may be accommodated as well.

As is well known, semiconductive materials exhibit electron quantumenergy bands and gaps there between (so-called “band gap”) resultingfrom, inter alia, two standing quantum wave functions Ψ(+) and Ψ(−). Thegap is the difference in energy between the lowest point of theconduction band (conduction band edge) and the highest point of thevalence band (valence band edge). As illustrated in FIG. 27 b, it hasbeen found that a co-planar array of graphite carbon fibers embeddedwithin a (doped) epoxy matrix exhibits semiconductive behavior in thedirection normal to the plane of the fibers. Conductivity ranges broadlyfrom roughly unity to 10 E-05 mho/cm, being largely a function oftemperature applied to the matrix. As previously indicated, the pressureand temperature applied at time of composite formation also may affectthe semiconductive properties (and even the conductive properties) ofthe matrix. The application of an electrical potential (V) across thethickness of the composite in the region 2804 induces electrontransition across the band gap. Transition of excited electrons to alower energy state generates the production of quanta having energycorresponding to the band gap (e.g., 0.01-0.1 eV), such quanta beingradiated from the region 2804.

The conductive carbon fibers 2806 present in and adjacent to thesemiconductive region 2804 are further utilized to conduct electricalcurrent to the semiconductive region 2804 through the property of planarconductivity of composite matrices described previously. Specifically,regions of generally coplanar carbon fibers are etched or otherwiseconstructed within the housing polyer matrix so as to form conductivetraces 2810 within the housing matrix itself, thereby obviating anyother types of conductors and the additional space, cost, and laborassociated therewith. Hence, the present invention advantageouslyemploys graphite or other composite structures which act both asembedded electrical conductors and semiconductors.

As shown in FIG. 28, the present embodiment of the smart device 2800includes a substantially cylindrical active semiconductive region 2804disposed generally around the outer periphery 2807 of the probe 2800.The active region 2804 comprises a plurality of graphite, fiber-basedlayers which are laminated upon and in communication with one another soas to form a “sandwich” of materials, the junctions of the sandwichcorresponding to p-n junctions within a traditional semiconductor. Acentral “optically” conductive layer 2805 disposed between the graphitecomposite layers 2811 is used as the medium for photon transport fromthe active region, thereby forming an effective annulus for photonemission from the front of the probe 2800. Population inversion withinthe medium may be selectively induced by the proper selection of themedium material and the application of the potential V+ 2810 across thejunction(s), thereby resulting in stimulated emission of quanta of thedesired energy.

Hence, the arrangement of FIG. 28 provides increased luminosity andphoton dispersion within the intestine when activated (as compared to a“discrete” semiconductor device such as LED or semiconductor laser),since the entire circumference of the active region of the housing isstimulated to emit photons of the desired energy.

In the illustrated embodiment, polyacrylonitrile is used in theformation of the fibers. Specifically, the compound is heated to formthe carbon fibers as is well known in the materials arts. This cancomprises a multi-step heating process which involves elevation oftemperature to between 400 degrees C. and 1300 degrees C. which formsaromatic carbon, although other processes may be used. Formation of thehousing/structural components themselves may be accomplished byresin-transfer molding (RTM), pultrusion, manual or automated layup, orother techniques of the type well understood in the field.

Autonomous Pressure Sensing Apparatus and Method

Referring now to FIGS. 29 and 30, yet another embodiment of theautonomous smart probe of the invention is described. In the instantembodiment, the probe 2900 includes a housing 2902 having one or moreapertures 2904 formed therein, the apertures receiving respective onesof miniature piezoelectric transducer elements 2906 adapted to sensepressure variations on the outer surface of the housing 2902. Thetransducer elements 2906 have a small facial area 2908 (on the order of15 mm²) and depth so as to be readily accommodated within the probehousing. The active portion 2908 of the transducer elements 2906 eachcomprise a piezoelectric ceramic compound of the type commonly used inacoustic and pressure sensing devices, the manufacture andcharacteristics which are well understood by those of ordinary skill.The piezoelectric devices generate a small but measurable voltage acrosstheir output as a result of pressure applied to their face 2908, theoutput voltage being a function of, inter alia, the facial pressureapplied.

The active faces 2908 of the transducer elements are disposed within theprobe housing 2902 in a generally radial, offset fashion so as to obtaindata from various different portions of the probe housing (therebyincreasing the probability of a representative sample), although manyother configurations may be used. The use of offset elements allows theoutside diameter of the probe to be smaller as well, since each elementmay occupy almost the entire diameter of the interior of the probehousing 2902, as shown in FIG. 30. The transducer elements 2906 arefurther securely held within the housing apertures using, for example,an epoxy of other adhesive which also acts as a sealant against ingressof fluid past the transducer element/aperture edge interface. Since (i)the probe housing 2902 is rigid and non-collapsible, (ii) the transducerelements are tightly secured within the housing 2902, and (iii), theopposing outer surface of the probe housing is abutted against theopposing intestinal wall, thereby generating a reaction force PR,pressure applied to any given transducer element face 2908 will begenerally reflected in the transducer element output voltage.

The electrical terminals 2914 for each transducer element are routed torespective conductive traces 2916 formed on the interior surface of thehousing 2902, thereby minimizing the volume used within the housing. Inone embodiment, transducer element output voltage is filtered 2950 toremove noise and undesired out-of-band components (e.g., high frequencynoise within the pressure waveform) and subsequently fed to an ADC 2952of the type previously described herein to generate a binary digitalrepresentation of the filtered transducer output voltage waveform as afunction of time (FIG. 30 a).

The multiple transducer elements 2906 of the probe further provideincreased level of statistical confidence in the results obtained fromthe different transducers. For example, if the standard deviationassociated with pressure measurements obtained from the varioustransducer elements 2906 at a given time is large, the data (or portionsthereof) may be suspect. Many other types of statistical analyses may beapplied as well, such analyses being well known in the mathematic arts.

Furthermore, the use of multiple transducer elements 2906 permits theapplication of coincidence logic (such as that described herein withrespect to FIG. 33 a). Specifically, an output voltage threshold valueis specified, the threshold voltage correlating to a given pressureapplied to the transducer face such as would result from peristalticcontractions of the subject's intestine. The coincidence logic (notshown) will produce a “high” output signal only upon the selectedtransducer elements collectively meeting the designated coincidencerequirement, such as ⅔ or ⅗. Hence, spurious pressure/voltage transientsaffecting one transducer element will mitigate the chance that aperistaltic contraction will be falsely indicated by the probe.

In the illustrated embodiment, the aforementioned filter circuit, ADC,coincidence logic, and any other related circuitry is disposed within anmulti-function integrated circuit (IC) 2970 such as the ASIC aspreviously described herein, although other configurations may be used.

Ultrasonic Probe

Referring now to FIGS. 31 a-g, another embodiment of the autonomoussmart probe of the present invention is disclosed. In this embodiment,the probe 3100 is adapted to obtain acoustic images and/or echo-locationinformation via an installed acoustic narrowband phased transducerarray. The smart probe 3100 includes a piezoelectric (e.g., “ceramic”)transducer array 3102 disposed on the front end 3105 of the probe whichis adapted to transmit and receive ultrasonic acoustic waves. Thetransducer array 3102 comprises a plurality of rows (m) and columns (n)to form an m×n array of ceramic elements 3106. The array 3102 of thepresent embodiment comprises a 16×16 array which, when overlayed ontothe circular form factor, produces about 200 distinct transducerelements 3106 (FIG. 31 b). The unique beamforming and electricalinterconnection arrangement of the array permits simultaneousbeamforming in two dimensions from a single aperture, as is described indetail in U.S. Pat. No. 5,808,967 entitled “Two-dimensional arraytransducer and beamformer” issued Sep. 15, 1998, and incorporated hereinby reference in its entirety.

The array 3102 is generally cylindrical in shape (i.e., circular frontalcross-section) so as to facilitate travel through the intestinal tractof the subject, although other shapes (and numbers of transducerelements 3106) may be used. The array 3102 is further disposed at thefront of the probe 3100 and mounted conformably therewith, such that theouter edge 3110 of the array conforms substantially with the housing3104 of the probe in that region. This arrangement allows for thelargest array diameter to be used with the probe, thereby increasing thenumber of elements 3106 in the array, the allowable aperture, and thespatial (and temporal) resolution thereof. The array dimensions areapproximately 11 mm in diameter by 8 mm depth. The probe is fabricatedusing the multi-stage “slicing” methodology disclosed in U.S. Pat. No.5,808,967, which has been adapted to the small dimensions involved by,inter alia, using a narrow aperture laser beam for cutting the ceramic“blanks”. Alternatively, en extremely fine micro-edge saw blade of thetype known in the microelectronic fabrication arts may be substituted.The use of such laser (or micro-edge saw) allows for extremely fine cuts(i.e., spacing) between the transducer elements 3106, typically on theorder of 0.001-0.002 inch (roughly 0.02-0.04 mm).

The electrical leads of the X-axis flexible printed circuits (XFPC) 3109and Y-axis FPCs (YFPC) 3111, which ultimately provide electricalconnection to the various elements 3106 in the array 3102, are disposedsuch that the free ends of their electrical leads 3107 are disposed inessentially radial fashion around the periphery of the array 3102, asshown in FIG. 31 c. The FPCs are fabricated from a suitable polymer(e.g., polyimide, aka Kapton®) using lithography techniques well knownin the semiconductor and circuit fabrication arts, thereby allowing avery fine array of electrical leads which are adapted to connect signalsto each of their respective elements 3106. The leads are, in oneembodiment, conductively bonded (such as by direct frictional contact,solder, or other means) to corresponding ones of longitudinally-orientedgraphite carbon fibers disposed within the polymer matrix of a“structural electronics” probe housing of the type previously described,into which the phased array 3102 is fitted. In another embodiment (notshown), the free ends of the FPC elements are conductively bonded torespective ones of (parallel) electrical traces formed on the insidesurfaces of the front portion of the probe housing proximate to thearray 3102. The traces are then routed to rear portions of the probe forelectrical contact with the appropriate distal leads of the PCBAspreviously described, or alternatively directly to the leads of theintegrated or discrete electronic components in the probe housing. Inyet another variant, conventional fine-wire (i.e., 38 AWG or smaller)conductors such as those manufactured by the Industrifill Corporation,are embedded in the thickness of the housing during molding or otherformation process, the latter forming electrical insulation between theconductors, which are terminated to respective ones of the arrayelectrical leads. It will be appreciated that yet other arrangements maybe used as well.

The operating center frequency of the array and system is 500 kHz(narrowband), although other frequencies may be used. Based on a fluidicvelocity of propagation of roughly 4300 fps, the wavelength of theresulting 500 kHz transmission is approximately 2.6 mm. In air (assumingthe intestine to be evacuated), the propagation velocity issubstantially reduced (about 1100 fps), and the wavelength afforded bythe 500 kHz signal on the order of 0.7 mm. Hence, the ultrasonicapparatus of the invention may be adapted to operated in either fluidicor gaseous environments within the intestine, although due to evacuationprocedures, it is anticipated that the gaseous (air) environment willpredominate. Accordingly, acoustic transmission through air is used asthe basis for the construction of the present embodiment.

A block diagram of the preferred embodiment of the two-dimensionaltransducer array is shown in FIG. 31 d. The individual Array elements3106 are electrically interconnected along front-side columns andback-side rows. Array elements 3106 are interconnected to the associatedbeamformer 3125, 3126 through 2-axis transmit/receive (T/R) switches3128. The transmit and receive 3125, 3126 beamformers may be eitherphase or time-delay beamforming networks of the type well known in theart.

The face width of each element is approximately one wavelength (λ),where λ is the acoustic wavelength in air (0.67 mm) of the desiredcenter frequency of 500 kHz. It will be recognized, however, that alarger or smaller number of transducer elements may be used (such as a32×32 array at 0.5λ yielding roughly 800 elements in circular formfactor), consistent with the extant technology for fabricating thearray. Note that to form beams with 4 degree beam width dispersion, anarray diameter of approximately 16 wavelengths is required, consistingof a 16×16 element array of approximately 200 elements. The back siderows 3122 and front side columns 3120 of the array elements areelectrically connected together along parallel lines of elements withthin acoustically transparent material, as shown in FIG. 31 c. It willbe recognized that while the rows and columns of the present embodimentare orthogonal, such need not be the case.

Each of the array X axis rows 3122 and Y axis columns 3120 are connectedto a T/R switch 3128 which, as controlled by a T/R logic signal 3131,electrically connects the sets of X and Y lines to respective X and Yreceive beamformers 3126 in the receive mode, and to X and Y transmitbeamformers 3125 in the transmit mode. When receiving, the array linesare connected through the T/R switch to receive beamformers 3126 whichreceive the electrical signals from the transducer lines while providinga low electrical impedance path (relative to the electrical impedance ofthe line of transducer elements) to signal ground on each X and Y line.When transmitting, the array lines are connected through the T/R switch3128 to the transmit beamformers. The transmit beamformers provide theelectrical transmit drive signals from a low impedance electrical source(relative to the electrical impedance of the line of transducer elements3106). This low electrical source/load impedance on each Y and Y line(i.e., low source impedance during transmit mode and low load impedanceduring receive mode) allows both simultaneous and independent access toeach X row 106 and Y column 104 for the application of transmitelectrical drive signals and the receipt of signals from each X row 3122and Y column 3120.

Furthermore, the arrangement of the present invention allows parallelsets of X and Y axis line arrays can be simultaneously and independentlyformed. X-axis transmit and receive line arrays are formed by theparallel electrical connection along the back side rows, along with thelow impedance signal ground on all of the front side Y-axis columns3120.

During signal receipt, the electrical signal present on each X-axis row3120 (with the front side low impedance path to signal ground)represents the sum of the received electrical signals of all elements ineach row. Most conventional ultrasonic/acoustic receiver amplifiersprovide a high impedance load to the receiving transducer. However, forthe 2-dimensional array application of the present invention, anamplifier has been developed for use in the receiving beamformer whichprovides a low impedance load while receiving. This is accomplished byconnecting each of the X and Y-axis lines to a virtual ground node (apoint having the same potential level as ground but not directlyconnected to ground) on the receiving preamplifier within the receivebeamformers. The signal current flowing into each virtual ground node isthe sum of the signal currents from all the ceramic elements in thecolumn or row. When receiving signals from a column, the column signalis independent of the row signals being simultaneously received due tothe low impedance load presented by the virtual ground on all rows.Similarly, when receiving signals from row, because of the low impedanceload presented by the virtual ground on all columns, this row signal isindependent of the column signals being simultaneously received.

During receive operation, electrical signals received on the X rows arephase or time delayed and combined in the X row receiver beamformer toproduce inclined receive acoustic beams in the Y direction.Simultaneously and independently, signals received on the Y columns andcombined in the Y side beamformer produce inclined receive acousticbeams in the X direction. Thus, through superposition of the X and Yaxis electrical and acoustic signals, 2-dimensional acoustic beamformation from a single planar array in both transmit and receive modesis achieved.

During signal transmission, transmit drive signals are applied throughthe T/R switch to the parallel X-axis back side electricalinterconnection lines from a transmit amplifier which has a low outputimpedance relative to signal ground. While the X-axis drive signals arebeing applied to individual X-axis line arrays, the entire Y-axis 16parallel line array face is maintained as a low impedance path to signalground (via the signal path through the Y-axis T/R switch 3128 a to thelow impedance Y-axis drivers of the Y beamformer) to ensure that theX-axis drive signal is imposed solely across the X-axis rows, and doesnot couple to the Y-axis side of the array. Similarly, while the Y-axisdrive signals are being applied to Y-axis line arrays, the entire X-axisarray face is maintained as a low impedance path to signal ground toallow signals to be independently applied the Y-axis without coupling tothe X-axis.

During signal transmission, phase or time-delayed signals applied to theX rows form inclined acoustic transmit beams in the Y direction (YZplane). Simultaneously and independently, phase or time-delayed signalsapplied to the Y columns to produce inclined acoustic transmit beams inthe X direction (XZ plane).

Thus, the low impedance associated with the transmit beamformer sourcespermits X- and Y-axis line transmit arrays to be formed simultaneouslyand independently by superposition of both X and Y axis transmit drivesignals.

The foregoing independent and simultaneous X row and Y column electricalaccess during both transmit and receive modes via the X and Y signallines allows the array to be used as a 2-dimensional array tosimultaneously and independently form multiple inclined acoustic beamset in both the X-Z and Y-Z planes. The beamforming operation in eachplane is the same as conventional 1-dimensional phased and/or time-delayarrays. Thus, the 2-dimensional beamforming operation is in general theequivalent of two overlaid 1-dimensional arrays, with one array rotated90 degrees from the other

Receive operation of the frontside (Y) columns with the backside rows3122 all coupled to signal ground in the X-axis receive beamformer willfirst be considered. Each set of four X-axis electrical signals (in the16×16 array) are connected to virtual ground nodes in the receiverpreamplifier of the receive beamformer to form a signal reference forthe backside rows, and phase shifted between adjacent line-arrays. Theimposed phase shifts compensate for those arising from the differentinter-element path lengths of the narrowband acoustic pulse incident onthe line arrays. The resulting signals will be in phase and, whensummed, will form a maximum acoustic interference pattern when receivinga wavefront arriving at a prescribed incidence angle. This maximumcorresponds to the central axis of one of the main lobes of the formedbeams. A second receive beam can be formed for incoming sound raywavefronts traveling in the −X direction and at an angle Φ with the Zdirection (at the predetermined incidence angle) by reversing the signof the imposed phase shift on the four signals and summing the signals.Since the set of four signal phases repeats for additional sets ofline-arrays, larger arrays can be implemented by summing the signalsfrom all sets of line-arrays to further enhance the interferencepatterns at the predetermined incidence. When additional sets ofline-array segments are utilized as described, the acoustic signal gainalong the predetermined incidence angle directions is increased, orcorrespondingly, the beamwidth in that direction is reduced, asadditional sets of arrays are added.

An equivalent beamforming method is to first sum all of the equal phasesignals from different array sets, then apply the imposed phase shiftsbetween the summed set of signals.

During the transmit mode, operation of the 2-axis array is similar tothe above described receive mode except the flow of signals is reversed.A long tone burst carrier frequency is applied to a phase shift transmitbeamformer, generating drive signals with different relative phases.These are applied to the parallel wired sets of Y columns from lowimpedance drivers. The imposed phase shifts will compensate for thosearising from the different path lengths between line arrays, and atransmitted acoustic signal interference pattern at a predeterminedincidence angle will be formed, corresponding to the center of one ofthe main beam lobes. Another transmitted beam can be formed at thenegative of the predetermined incidence angle (relative to the Zvector). incidence angle by reversing the sign of the imposed phaseshift as previously described.

Receive and transmit operation in the Y-axis is the same. Whenconsidering signals applied and received from the backside rows, thefrontside columns are coupled through a low impedance to signal ground.The presence of the low transmit drive and receiver load impedance toground on each side results in fully independent X and Y axis operation.From superposition of the X and Y axis signals, it can also be seen thatboth axes (i.e., rows and columns) can be in operation simultaneously.

The above described 2-axis beamforming technique using fixed phasedelays in forming narrow transmit and receive beams and is referred toas a “two-dimensional phased array” transducer. It is suitable for usein narrowband applications which transmit a single frequency(narrowband) long tone burst.

One embodiment of the time-delay receive mode beamformer circuitry usedin conjunction with the array 3102 of the present embodiment isdescribed in greater detail in U.S. Pat. No. 5,808,967, previouslyincorporated herein. Such circuitry is also well known to those ofordinary skill in the acoustic hardware and signal processing arts, andhence other variants may be used consistent with the invention toprovide equivalent results. As illustrated in FIG. 31 e, the circuitry3170 generally comprises the respective transmit/receive beamformer3125, 3126 (transmit “Y” beamformer shown), which comprises a pluralityof signal amplifiers 3172 and associated virtual grounds 3174, eachamplifier 3172 supplying a signal to a respective row of transducerelements 3106 (e.g., “Y” axis elements). The amplifiers of the presentembodiment are constructed using a push-pull field-effect transistorstage 3180, as shown in FIG. 31 f, although other arrangements may beused. Respective phase shifters 3176 of the type well known in theelectronic arts are disposed on the input of each amplifier whichtemporally (phase) shift the transmit signal 3178 for successive arrayrows/columns of array elements 3106 as previously described in order toform angularly disposed beams relative to the array face. Similarly, inthe “X” dimension, the application of similar signals to thecolumns/rows on the opposite face of the transducer elements inducesbeam formation with respect to the X dimension of the array, suchsignals advantageously being applied simultaneously with the “Y” axissignals as previously described.

It is noted that due to the extreme space limitations of the probe ofthe present invention, two primary hardware environment approaches areused to implement the ultrasonic functionality described above: (i) theuse of a highly integrated, “SoC” device with macro function blocksadapted for ultrasonic signal processing/beamforming (FIG. 31 g); and/or(ii) substantial “off-probe” beamforming processing and signalprocessing of acquired ultrasonic data.

As is well known, significant signal processing capability is foundwithin the conventional fixed point or floating point DSP or RISCprocessor. In order to economize on space within the probe otherwiseconsumed by comparatively bulky DSP packages, one embodiment of theinvention incorporates an extensible RISC processor core as describedwith respect to FIG. 16 herein which has an instruction set andconfiguration optimized for beamforming and signal processingcalculations (e.g., FFT) associated with ultrasonic devices such asthose of FIGS. 31 a-g. In this fashion, the processor core is made withreduced gate count, and accordingly the ASIC in which the core isdisposed has reduced size and power requirements.

Alternatively, much of the signal processing associated with theultrasonic system may be transmitted off-probe, either real time or indelayed fashion (such as, for example, through a data buffering systemwhich allows for transmission across communications links having reducedbandwidth compared to the ultrasonic data being generated, or throughstorage of information in memory for download after excretion of theprobe, as previously described). Real-time transmission may beaccomplished, for example, via the inductive data transfer circuitpreviously described herein, or via the “Bluetooth” RFtransceiver-equipped ASIC of FIG. 16. Accordingly, in one embodiment,after the “raw” unprocessed acoustic echo data is received by the probetransducer array 3102, it is buffered (for example in a RAM buffermemory as previously described) and subsequently transmitted over thewireless data interface to the MCD 804 or other remote device adapted toreceive the data. A digital signal processor (DSP) resident in theremote device, along with attendant memory, software, and displaydevices well known in the electronic arts, subsequently perform thebeamforming computations previously described, and further process thedata to generate a video image (and/or audio representation) of theechoes received by the transducer array. The remote device, via reverselink communications to the probe, can also advantageously be used to“steer” the beams of the phased array to obtain imaging of particularsolid angles within the field of ensonification of the array at thatgiven time. Steering of the beams is accomplished based on the relativetiming of drive signals applied to various transducer elements 3106 ofthe array 3102, as previously described.

Yet other configurations are possible, however. For example, thefield-effect transistor(s) (FET) used in the beamformer and amplifiercircuitry. 3172 previously referenced herein may be embodied in the“structural electronics” housing of FIG. 28, thereby obviating the useof either a discrete PCBA-mounted or integrated FET device.

It will also be recognized that while the present embodimentincorporates a unitary phased array transducer and associatedbeamforming and processing adapted to generate ultrasound images, otherless sophisticated approaches may be used to accomplish less demandingobjectives. For example, in order to accomplish simple ultrasonicecho-ranging within the intestine (such as to determine the range fromthe probe to an intestinal obstruction or artifact), a single non-phasedtransducer element could be used to radiate pulsed ultrasonic waves ofthe desired frequency and receive echoes resulting therefrom, theinterval between transmission and echo return being correlated to therange of the obstruction/artifact based on wave propagation speed.Alternatively, such transducer could be used to generate ultrasonicwaves and receive echoes which are processed for Doppler shift inducedby movement of the intestine wall and/or probe (the latter due, forexample, to the peristaltic action of the intestine).

Antigen Detection

Referring now to FIG. 32, an improved apparatus and method for detectingthe presence of certain substances or antigens is disclosed. As usedherein, the term antigen generally refers to any substance or entitywhich promotes a response in vivo, and more specifically to substances(such as proteins, polysaccharides, or lipoids) which induce, whetherdirectly or indirectly, the production of one or more antibodies orproteins as a response to the antigen.

In the embodiment of FIG. 32, the apparatus comprises an autonomousprobe 3200 having one or more sensing arrays 3202 disposed at or nearthe surface 3206 of the probe (accessible to the intestinal epitheliumand fluids present in the intestine). The sensing arrays 3202 areexposed to the tissue of the intestine wall during travel of the probe3200, allowing each sensing array to detect the presence of antigen(s)3208. In the variant of FIG. 32, the sensor arrays 3202 comprise aplurality of molecular receptor sites 3210 which are bonded to anorganic or other suitable substrate adapted to retain a plurality ofreceptor molecules attached thereto. The attachment of receptormolecules to various substances is readily accomplished using any numberof available methods known to those of ordinary skill, and accordinglyis not described further herein. The receptor molecules 3210 arespecially configured to receive only one target molecule (or class ofmolecules) corresponding to the desired antigen 3208. For example, Tumornecrosis factors (TNF) alpha and beta are examples of cytokines whichact through TNF receptors to regulate numerous biological processes inthe human body, including protection against infection and induction ofinflammatory disease. The TNF molecules belong to the TNF-ligand family,and act together with their complementary receptors, the TNF-receptorfamily. Such TNF ligands include TNF-a, lymphotoxin-a (LT-a, also knownas TNF-b), LT-b, FasL, CD40L, CD27L, CD30L, 4-1BBL, OX40L and nervegrowth factor (NGF). TNF receptors includes the p55TNF receptor, p75TNFreceptor, TNF receptor-related protein, FAS antigen or APO-1, CD40,CD27, CD30, 4-IBB, OX40, NGF-receptor, and low affinity p75. It will bereadily appreciated, however, that myriad ligand/receptor families maybe used with equal success consistent with the present invention.

The sensing arrays 3202 of the probe 3200 may selectively uncovered viaa series of apertures 3212 using a shutter arrangement 3211 such as thatdescribed previously herein with generally respect to FIG. 18. Hence,the arrays 3202 are shielded or covered from direct exposure to theintestinal tract (including any gastric substances) until the shutters3211 are opened. The shutter apertures are also optionally covered witha readily dissolvable non-toxic compound (such as the aforementioned“gel cap” material) which acts as a sealant for the apertures beforeshutter opening. Target molecules present in the intestinal wall orassociated fluids (if any) are received at the receptor sites andcaptured on the arrays 3202 while the shutters 3211 are open.Subsequently, the shutters 3211 are shut via on-probe or externallygenerated signal (as previously described) so as to avoid furthercontamination of the arrays during the remaining length of theintestine, and the probe ultimately excreted from the subject'sintestine. The probe 3200 is then retrieved and analyzed using wellknown laboratory techniques to determine the presence of the targetmolecules on the array(s). FIG. 32 a graphically illustrates theforegoing methodology.

Liquid (such as water for example) may also be introduced if necessaryeither orally, or via the probe 3200 itself using apparatus such aspreviously described herein with respect to ligand or radionuclidedelivery, at an appropriate time with respect to probe travel in theintestine so as to further facilitate mobility of the target moleculeswithin the intestine and array(s).

In another embodiment, electrical conductivity (or alternativelyresistivity) is measured across a membrane or other device disposed onan array proximate to the outer housing of the probe and such that it isexposed to the intestinal wall/fluids; the presence of target molecules(analytes) is reflected in changes in the conductivity due to, interalia, ion diffusion. See U.S. Pat. No. 5,874,316 entitled “Receptormembranes and ionophore gating” issued Feb. 23, 1999, incorporatedherein by reference in its entirety, which details a membrane, theconductivity of which is dependent on the presence or absence of ananalyte. The membrane of the '316 patent comprises a closely packedarray of self-assembling amphiphilic molecules and multiple ionophorecomponents. A receptor molecule reactive with the analyte is provided onone of the ionophore components. The binding of the analyte to thereceptor molecule causes a change in the relationship between theionophore components such that the flow of ion across the membrane isprevented or allowed. One or more such membrane-based devices are usedin this embodiment of the probe as detection arrays. Change inconductivity is readily measured across the membrane by monitoring thepassage of electrical current through the membrane using, for example,any well known conductivity cell arrangement (e.g., Wheatstone bridge)which may be included within the probe, the electrical power supplied bythe on-probe or off-probe power sources previously described.

In yet another embodiment, the detection of the target molecules isperformed using a bio-electronic sensor comprising a thin, electricallyconductive surfactant polymeric layer to which members (e.g., receptors)of specific binding pairs are bound. Specific binding of targetmolecules (or “competitor” molecules) to the bound specific binding pairreceptor results in a change in the conductivity of the polymer. Theresultant change in conductivity is related to the presence of thetarget molecule in the sample. See U.S. Pat. No. 5,491,097 entitled“Analyte detection with multilayered bioelectronic conductivity sensors”issued Feb. 13, 1996, also incorporated herein by reference in itsentirety.

As yet another alternative, a plurality of “bridges” of receptormolecules disposed between pairs of inorganic conductive terminals 3301are used to identify the presence of target molecules, as illustrated inFIG. 33. The receptor molecules 3330 are bound to the terminals 3301using a thin conductive surfactant polymer layer such as previouslydescribed, or alternatively via direct bonding of the receptor complexto the inorganic metal atoms of the terminals as recently demonstratedat University of Texas at Dallas. When the bridge 3302 is completed viathe reception of the target molecule(s) 3302 between the two receptormolecules 3330, the electrical conductivity increases (or conversely,the resistance decreases) due to outer shell electron transfer acrossthe target molecule(s) and receptor(s). The conductivity increase (orresistance decrease) is detected by conductivity circuitry 3306 withinthe probe, which comprises a potential source 3307 applied across theterminals, current sensing circuit 3308 of the type well known in theelectronic arts, and analog-to-digital converter (ADC) 3310, the latterboth optimally disposed within the “front end” of the customized ASIC ofFIG. 16. The ADC 3310 converts the analog voltage values generated bythe current sensing circuit 3308 to binary digital format for subsequentprocessing by other components in the ASIC (e.g., processor core andassociated embedded conductivity analysis algorithms). In theillustrated embodiment, a plurality of parallel bridge circuits 3321 areprovided, and coincidence logic 3320 is used to help avoid detection of“false positives” due to any number of sources including inadvertentreception of non-target molecules on one or more bridges, etc.Specifically, the coincidence logic 3320 comprises a logic gate network3324 having a two-out-of-three (⅔) coincidence as illustrated in FIG. 33a. The digitized conductivity values output from the ADC circuitry 3210associated with each conductivity channel 3321 are compared using acomparator function within the ASIC, or alternatively using softwarealgorithms running on the ASIC core, to a predetermined threshold level(or other criterion) to determine whether one or more target moleculeshave been received by the receptors 3304 for each channel. If thethreshold and/or other criteria are met, a logic “high” is output by thecomparator/core for that channel. Such information may then be stored inthe probe along with a “time-stamp” generated by the processor, and/orstreamed off the probe via one of the aforementioned communicationchannels (RF, etc.) As shown in the logic state table 3335 of FIG. 33 a,⅔ coincidence is effected for these comparator/core output signals.Other coincidence schemes and/or numbers of conductivity channels mayalso be substituted if desired. Furthermore, the coincidence logicdescribed above may be applied to multiple channels of other types ofdetectors within the probe, including for example the (i) conductivitydetecting membrane of the '316 patent; and/or (ii) bioelectronic sensorwith electrically conductive surfactant polymeric layer of the '097patent, both previously described herein.

In another embodiment, the conductivity values of the parallel bridgechannels 3321 are digitized and multiplexed via a multiplexer (MUX) andanalyzed by coincidence detection algorithms running on the ASIC core,the latter being adapted to perform such analysis. Many other approachesfor utilizing on-probe assets for measuring conductivity are alsopossible. Furthermore, the “raw” conductivity data may also betransmitted off-probe via one of the aforementioned data communicationpaths, thereby facilitating analysis of the data off-probe in real time.

Secondary Probe Deployment

Apparatus and methods for utilizing “secondary” special function probeswithin a living subject are now described. The aforementioned smartprobe (“primary” probe) is used to deploy one or more special functionsecondary probes within the subject's intestinal tract, the specialfunction probes being adapted to perform a variety of therapeutic oranalytical functions including, for example irradiation of tissue withinthe subject's intestine, biopsy, ultrasonic analysis, or timed releaseof ligands or other pharmaceuticals. The primary probe of the presentembodiment advantageously may be used for, inter alia, various supportfunctions including positioning and deployment of the secondary probe,power supply, communications/data streaming functions, thereby relievingthe secondary probe of these functions, and allowing the latter to beless complex and/or smaller in profile. As described in greater detailbelow, the secondary special function probes may further be adapted tomaintain a substantially constant location within the intestine of thesubject for at least a period of time, thereby facilitating extendedoperations (e.g., irradiation or ablation) relating to specific tissuelocations within the intestine. Other such specialized functions mayalso be performed using the secondary probes. While the followingdiscussion is cast in terms of a separable secondary probe adapted forextended irradiation of a portion of the intestinal epithelium, it willbe recognized that myriad other configurations and functions may beemployed consistent with the invention, such functions including,without limitation, (i) positron irradiation in support of PET scanning,(ii) delayed or extended delivery of ligands or other agents, (iii)tissue biopsy, (iv) peristaltic pressure measurements, (v) ultrasonicimaging, (vi) antigen detection, (vii) temperature detection, (viii)magnetic field therapy, and (ix) laser or microwave ablation.

In one exemplary embodiment, the primary smart probe includes asecondary or “trailer” probe of the general type described previouslyherein with respect to FIG. 25. The secondary probe is selectivelyseparable from the primary probe by the operator, or upon the occurrenceof a predetermined condition or set of conditions, as has beenpreviously described with respect to the variety of foregoingembodiments. This severance is accomplished by any number of means,including, as in the present embodiment, electrical energization of thesolenoid assembly in the primary probe which causes release of thesecondary probe through retraction of a retaining pin (not shown)holding the secondary probe to the umbilical between the primary andsecondary probes. Alternatively, the use of other mechanical, chemical,or electrical means may be employed, as will readily be apparent tothose of ordinary skill.

The trailer probe of the present embodiment is further equipped tosubsequently expand and/or “wedge” itself within the intestine, suchthat it remains effectively stationary for a period of time while theprimary probe continues down the intestinal tract via peristalsis. Probeexpansion may be accomplished using the configuration previouslydescribed herein with respect to FIG. 25 (i.e., inflation), oralternatively through use of salient structures (e.g., scoops)projecting from the surface of the otherwise un-deformed probe housing.

The therapy agent (such as, for example, a radionuclide source) isdisposed within the trailer, thereby allowing the extended applicationof the therapeutic action to the desired intestinal tissue. Upon commandfrom the operator and/or the occurrence of a predetermined event, thetrailer probe alters its shape/configuration (e.g., deflates, orretracts the salient structures), thereby allowing it to subsequentlyproceed down the intestinal tract via peristalsis. In one variant, thetrailer probe comprises a microchip pharmaceutical delivery device ofthe type previously described herein which has been adapted forcontrolled release of pharmaceuticals or other agents to a localizedregion of the intestine for an extended period.

Microwave Ablation

Referring now to FIGS. 34 a-34 b, yet another embodiment of themulti-probe system 3400 of the invention is disclosed. As is well knownin the radiotherapy arts, electromagnetic energy may be used to ablatetissue. Direct ablation (e.g., the application of electromagnetic energydirectly to target tissue within the intestine from a source ofelectromagnetic energy disposed on-probe) has been previously discussedherein. However, in certain applications requiring more significantradiated power or thermal energy than that produced by the on-probesemiconductor laser diode previously described, off-probe sources ofsuch energy are needed. Accordingly, the present invention contemplatesthe use of an external “pumping” source of microwave energy whichinteracts with a resonant cavity probe positioned in vivo to ablatetissue. In the illustrated embodiment, the secondary probe 3402comprises a metallic target structure 3403 optimized to resonate,reflect, and/or absorb electromagnetic radiation (e.g., microwaves ormillimeter waves) incident on the target under certain aspects.

As shown in FIG. 34, the resonant cavity 3406 of the target structure3403 is generally constructed such that its dimensions and physicalproperties (e.g., material of construction, presence and positioning ofdielectrics within the cavity, etc.) act to (i) resonate incidentmicrowave energy having frequency on the order of 30 GHz nominal; or(ii) induce high dielectric losses within the probe, thereby causingsignificant heating thereof. The selected cavity is a transverseelectric 1, 0, 2 mode (TE₁₀₂) cavity with interior dimensions ofapproximately 10.2 mm×22.8 mm×10.2 mm, with the latter 10.2 mmcorrelating to the “Z” dimension 3405 of the cavity based on 29.4 GHznominal, although other dimensions may be used. This symmetry betweenthe Y and Z dimensions of the cavity allows the cavity to performeffectively identically with respect to two axes. Energy is introducedinto cavity 3406 via one or more apertures 3407 disposed at the side(s)of the cavity when the probe is properly oriented with respect to themagnetron (described below), and to some degree through directtransmission through the cavity walls. Losses due to Joule heating inthe metallic cavity walls, radiant heating of the materials surroundingthe cavity structure, energy absorption in high-loss dielectricspositioned within the cavity, or leakage of energy from aperturespresent in the walls of the cavity, transfer both heat andelectromagnetic energy to the tissues surrounding the cavity 3406 andprobe 3402 which are to be ablated. Heat energy transfer occurs by,inter alia, conduction between the cavity and the outer housing 3431 ofthe probe 3402, and emission of infrared radiation thereby.Additionally, leakage of the millimeter wave energy by the cavity (aswell as direct incident and reflected millimeter wave energy) inducesexcitation and heating of surrounding tissue cells and their molecules.

The construction of microwave resonant cavities is well known in thearts. See, for example U.S. Pat. No. 5,712,605 entitled “Microwaveresonator” issued Jan. 27, 1998, and U.S. Pat. No. 6,131,386 entitled“Single mode resonant cavity” issued Oct. 17, 2000, both incorporatedherein by reference in their entirety, which describes the constructionof various types of microwave resonators, the general principles ofwhich are applicable to the resonator cavity 3406 of the presentembodiment. As is well known in the art, Q factor is defined as themicrowave frequency of the resonator times a ratio of the microwaveenergy stored in the resonator and the average microwave power loss inthe resonator. As is also known, Q factor of traditional metalliccavities can be considerably affected by using dielectric materialsproperly placed within the cavity. Furthermore, through the use ofhigh-loss dielectrics, the energy absorbed in the dielectrics may beadjusted. The Q factor (and relatedly the ratio of transmitted toreflected power for the cavity) in the present embodiment is selected soas to produce the desired degree of thermal heating of the cavity, aswell as ablation of surrounding tissue due to reflected microwaveenergy. For example, in one embodiment, a fairly low Q factor resonatoris used in conjunction with the aforementioned dielectric materials toinduce minimal energy storage within the resonator under certain spatialorientations of the probe and incident microwave energy.

It will be readily appreciated that the physical dimensions andconfiguration of the cavity 3406 of the invention may be variedsignificantly in order to achieve the desired objectives. Accordingly,one embodiment of the invention utilizes a substantially rectangularstructure (e.g., parallelpiped) for the cavity 3406 as previouslydescribed. For resonance in the rectangular (Cartesian) cavity, thefollowing relationship must be satisfied: (18-129 of Reitz)

Where:

C=propagation speed

ω=angular frequency

E_(x)=Electric field vector component in x direction

The resonant frequencies of such cavity are given by:k _(x) ² +k _(y) ² +k _(z) ²−ω² /c ²=0

Where k_(x,y,z)=magnitude of wave vector in x,y,z directions

Other configurations may also be used. For example, in a secondembodiment, a right circular resonant cavity is used. This configurationhas the advantage of conforming substantially well with the outerhousing 3431 of the probe 3402, thereby mitigating the creation ofcomplex reflections within the probe structure. For a right circularresonant cavity, Bessel functions of the type well known in themathematical arts are used to determine the physical dimensionsconfiguration satisfying the required boundary conditions.

Furthermore, discontinuities between media of the probe 3402, includingthe interface of the cavity walls 3420 and the outer housing of theprobe 3402 are also considered with respect to the complex dielectricconstant (j) for determination of the transmission/reflection ratio ofthe probe. Accordingly, in yet another of the probe, a cylindricalcavity is utilized with a high-loss dielectric protective coating. Inyet another embodiment, the cavity 3406 is filled with a high-lossdielectric fluid in order to affect Q.

The microwave energy incident on the probe 3402 is generated by aconventional magnetron device of the type well known in the electricalarts, and accordingly is not described further herein. However, in orderto mitigate collateral ablation or EM radiation dose to healthy orotherwise non-targeted intervening and surrounding tissues, the +/−29.4GHz microwave beam is collimated and focused using a conventionalrectangular cross-section transverse electric 1, 0 mode (TE₁₀) waveguidehaving nominal dimensions of 10.2 mm and 22.8 mm, for a maximumwavelength of approximately 4.6 cm (approx. 6.5 GHz), although otherdimensions may be substituted. As is well known, the path attenuationassociated with the propagation of the microwave energy is proportionalto both the square of the distance between the radiating device andreceiver, and the frequency, as well as the character of any interposedmedia. Hence, the power radiated by the magnetron is selected so as toproduce the desired transmitted and reflected power levels from theresonant cavity of the probe 3402 when disposed in vivo within theintestine, without significant dielectric losses in the surroundingtissues which otherwise would result in collateral tissue ablation. Thepresent invention also contemplates the variation of such power level(e.g., through temporal pulsation, such as by generating a microwavepulse train of period t, and/or through control of the field strengthapplied to the magnetron), as well as the frequency of the radiationemitted by the magnetron, thereby allowing the user to “tune” the degreeof resonance within/reflection by the cavity 3406 and target 3403, andaccordingly the ablation energy reflected/radiated from the probe invivo. The dielectrics (if any) used with the probe are also be selectedso as to produce the desired losses within the probe.

The present invention further contemplates the use of a variablegeometry resonance cavities in which one dimension (e.g., “Z”) isvariable with the probe in vivo. As the critical dimension of the cavity3406 is varied, it's resonance properties (and Q factor) are varied,thereby allowing for fine-tuning of the cavity for the desiredtransmission/reflection coefficient and ultimately ablation of thesurrounding tissue.

It will further be recognized that pulsed or CW electromagneticradiation (e.g., millimeter waves, IR, or coherent light energy) or evenultrasonic energy may be used consistent with the nanostructures (e.g.,fullerenes) and microparticles of the present invention for theenhancement of drug delivery in, inter alia, solid tumors. As previouslydescribed, the particles can be attached to molecules (e.g., antibodies)targeted for specific antigens present in tumor vasculature, therebypermitting selective delivery to the walls of the blood vessels of suchtumors. See, for example, U.S. Pat. No. 6,165,440 entitled “Radiationand nanoparticles for enhancement of drug delivery in solid tumors”issued Dec. 26, 2000 and incorporated herein by reference in itsentirety, which details perforation of tumor blood vessels,microconvection in the interstitium, and perforation of cancer cellmembrane, via cavitation induced by the selective application of pulsedelectromagnetic energy or ultrasonic waves.

Diagnostic Apparatus and Methods

Referring now to FIGS. 35-37, improved apparatus and methods forreviewing data generated by the aforementioned probes and diagnosing thesubject based on this data are disclosed.

It will be recognized that the phrase “received from the probe” orsimilar is meant to include direct or indirect receipt of data from theprobe, whether in real time or not, whether directly from the probe orone of its components or via other external or intermediary devices.Hence, such terms are merely expedients for describing any one of amyriad of different data flows from the probe.

Furthermore, as used herein, the terms “snapshot” and “frame” are meantto loosely refer to the concept of a collection of image datacorresponding to an image formed by a sensor. For example, where aninterlaced display is used, such frame may comprise a plurality of bytesof data, or a data packet of finite length. Hence, these terms are in noway limiting or specific to any particular technology, but rathergenerally applied to an aggregation of sensor data comprising all orportion of an image with some degree of temporal correlation.

As described below, various aspects of the present invention areembodied in the form of one or more computer programs (including“software” and “algorithms”). Such program(s) may be rendered invirtually any programming language/environment including for example C,C++, Java, Fortran, Basic, Visual Basic, Unix, Perl, CORBA, or any othermedium capable of reasonably implementing such a functionality. Forexample, in one exemplary embodiment, the software comprises a “C” basedcomputer program adapted to run on a conventional stand-alonePentium-based microcomputer, the microcomputer having a direct link tothe screen or display device. However, it will be recognized that othersoftware and/or hardware environments may be utilized consistent withthe invention and user's particular needs. For example, the software maycomprise an object-oriented distributed program having client and serverportions distributed on respective client and server devices, therebyfacilitating transmission of data from one location to another, oralternatively analysis at one location, and viewing at another aftertransmission thereto. As used herein, the term “client device” includes,but is not limited to, large-screen displays, personal computers (PCs),whether desktop, laptop, or otherwise, personal digital assistants(PDAs) such as the Apple Newton®, “Palm®” family of devices, handheldcomputers such as the Hitachi “e-Plate”, Motorola EVR-8401, J2MEequipped devices, cellular telephones, set-top boxes, or literally anyother device capable of interchanging data with a network. Such devicesmay interface using wired or optical fiber mechanisms such as an IEEEStd. 802.3 Ethernet interface, Digital Subscriber Line (DSL), V.90modem, DOCSIS modem, hybrid fiber-coax (HFC) cable, or alternatively viawireless mechanisms and protocols such as IS-95/CDMA-2000, Bluetooth™,IrDA interface, IEEE Std. 802.11(a) or (b), Wireless ApplicationProtocol (WAP), GPRS, GSM, third-generation or “3G” systems, or anyother of myriad data communication systems and protocols well known tothose of skill in the communications arts. Creation of such computerprograms and porting to the various hardware environments referencedabove is readily accomplished by those of ordinary skill in theprogramming arts, and accordingly is not described further herein,except with regard to the specific attributes and aspects of the presentinvention.

In a first exemplary embodiment (FIG. 35), improved data processing andreviewing apparatus 3500 is disclosed which allows the physician orcaregiver to efficiently analyze data obtained from a subject. Theapparatus 3500 includes digital data processors 3502 (i.e., amicroprocessor and DSP in data communication therewith), a mass storagedevice 3504 (e.g., Ultra-ATA or SCSI drive, CDROM, etc.), random accessmemory 3506, display device 3508, input device 3509 (e.g., joystick,mouse, keyboard, etc.), and specially adapted computer program (notshown, yet described below) for processing data obtained from the probe.In the present context, processing of video data (i.e., data visible tothe human eye) is described; however, it will be appreciated that theinvention and associated processing described herein may be adapted toautofluorescence data as previously described herein, as well asnon-visible types of radiation such as IR and UV. Furthermore, some orall of the components of the apparatus 3500 may be incorporated into theMCD previously described herein, or similar devices.

Motorola MSC-8101/8102 “DSP farms” are chosen as the digital processors3502 for the present embodiment due to their extremely high performanceand use of parallel processor cores, although other devices such as forexample the Texas Instruments TMS320C6x or Lucent DSP16000 series may beused for the signal processing functions.

As shown in FIG. 35 a, the display device 3508 includes a screen 3510which in the present embodiment is enlarged relative to the normalcomputer display to permit easy viewing by the physician, although thisis not a requirement. The screen 3510 is, through data processing andelectronics well known in the electronics and television arts, dividedinto a plurality of contiguous display portions 3511 wherein differentimages can be viewed simultaneously in the different portions 3511(i.e., “mosaic” display). This split or divided screen approach issimilar to the well known “picture in a picture” or PIP televisiontechnology or minicomputer “windowing” in a Windows® environment, yetthere is no overlap between the various portions 3511 in the presentembodiment. It will be recognized that while a six-portion screen isshown, the screen (and data) may be divided into most any number (n) ofportions, whether whole or fractional, and some degree of overlap may beused if desired.

The software associated with the apparatus 3500 processes the image datastream received from the probe via the communications protocol into acorresponding plurality (e.g., 1/n) of data streams for display onto thevarious portions 3511 of the screen 3510. Such processing can beaccomplished after-the-fact by simply knowing the total run length L ofthe data, and dividing by n, or if the data is streamed in real time (ornear-real time), by delaying the display of the data until anextrapolation of probe travel time is made (such as by measuring theprogress of the probe over a given time interval t, and thenextrapolating this value out to a total run length L_(e), and thendividing the streamed data accordingly.)

As an example of the latter, consider the case where the probe isintroduced into the intestine of the patient, and enters the duodenum atrelative time t=0. The probe is then observed to propagate through theintestine at a rate of X cm/hr. Knowing total intestinal tract length(approximate) as Y, the system can then, based on these inputs from theoperator, extrapolate the total duration of traversal by the probe asY/X hours. Assume that two (n=2) portions 3511 are desired for thescreen view. The system 3500 then knows that to run two parallelsegments of roughly equal duration on the screen 3510, it must take thetotal duration Y/X and divide by n=2, to produce two segments of Y/2Xduration. Hence, the system collects the streamed data until the systemtimer reaches t=Y/2X, at which point, the actual (real time) incomingdata is allocated into one portion 3511 of the screen, while the storeddata segment representing data obtained from t=0 through t=Y/2X isdisplayed on the second screen portion 3511. The user is presented withtwo parallel video streams, one from stored data and one in real time,which will co-terminate at approximately the same time. Hence, the usercan advantageously view data of length Y/X hours in only approximatelyY/2X actual time.

As will be recognized, the system 3500 of the present invention can alsobe configured to perform the foregoing calculations based on user input(i.e., number of portions desired, total patient intestinal tractlength, etc.) and automatically provide the user with an indication whenthe viewing time will begin, so as to obviate wasted physician time.Such indication may be coupled to a warning mechanism (e.g., audiblealarm, pager, cellular telephone, etc.) to alert the physician of theimpending “start” time for monitoring. Alternatively, the system 3500may be programmed to alert the viewer after all image processing(described below) has been completed.

Furthermore, more complex models of intestinal propagation can be usedas the basis of the calculation, such as where a non-linear rate ofpropagation occurs in various regions of the intestine. As a simplisticexample for illustration, consider the instance where small intestinepropagation rate is double that of large intestine rate. Knowing therelative lengths of each part of the intestine, the aforementionedcalculations can be adjusted to compensate for the “start” point ofscreen monitoring. Furthermore, heuristics, statistical data, orempirical data previously derived from the patient being monitored (orother single patients or groups of patients) may be used as the basisfor the aforementioned calculations by the system algorithm.

In one exemplary variant, the software of the system 3500 divides apre-existing data stream of finite length L into portions of data eachhaving length L/n. Hence, for example, where a four-hour or 240-minutedata stream (at real time speed) is recorded from the subject duringcapsule propagation through the intestine, the software of the presentinvention divides this four-hour stream into six forty-minute segments,each allocated to a different portion 3511 of the screen 3510. Divisionof the data stream may be according to a frame or packet index count,via queue or buffer mechanisms, or alternatively based on the physicaladdresses within memory where the streamed data is stored, or any numberof other well known techniques. The allocation of data stream segmentsto screen portions 3511 may be according to any desired scheme,including for example (i) increasing row-column temporal (i.e., thefirst portion 3512 displays the earliest segment, while the next portion3513 to the right in the same row, discloses the next temporal segment,and so forth); (ii) priority (i.e., those segments corresponding to whatare identified by the physician or other means as the most likelyregions of the intestine for disease are disposed in priority order onthe screen, such that the reviewing physician can preferentially viewone corner or region of the screen 3510 and periodically scan the otherscorresponding to the “lower risk” portions of the intestine); (iii)random (i.e., order selected according to output of seeded pseudo-randomnumber generator, so as to avoid predisposition of physician or priorknowledge to affect diagnosis); or (iv) inversion (e.g., wherein a“central” point within the intestine, and hence the data stream, is usedas the basis for n/2 segments displayed in forward motion in sequence,and the remaining n/2 segments displayed in reverse motion in sequence,such that the viewer is effectively presented with data mimicking twoprobes within the intestine converging on a central point, the secondprobe “virtually” propagating upwards through the intestine or againstthe peristaltic action of the intestine). Myriad other display schemesare possible, the foregoing being merely illustrative of the broaderconcepts of the invention.

The individual portions 3511 of the screen 3510 may also be supported byseparate software processes, threads, or objects (depending on thesoftware environment chosen), each individually controllable by theuser. For example, in one exemplary embodiment, the software of thesystem 3500 is adapted to allow the user to select an individual portion3511 of the screen during viewing, such as by using the attachedcomputer mouse 3509 or other input device, and varying the properties ofthat portion. Specifically, by “right-clicking” on the mouse 3509 afterthe user has selected a given portion 3511, the user is then presentedwith a menu bar or window of the type well known in the software artswhich includes a plurality of options for that portion. Such options mayinclude, inter alia, common video viewing functions such as “fastforward”, “pause”, and “reverse”, as well as other functions such as“zoom”, zoom-pan, image enhancement, digital whiteboard (activating alight pen or similar means for annotating the display for later use orcontemporaneous collaboration via a data network interface), save/print,and the like. Myriad types of well known user interfaces which providethe physician with control over the displayed images may be employedconsistent with the invention.

The use of a larger sized screen 3510 of the illustrated embodiment alsopermits the physician to clearly visualize each of the individual imagesas if they were only viewing that image. Conventional CRT, flat-screen,HDTV, or similar technologies may be utilized as desired in providingand rendering the images. Hence, in the illustrated embodiment, a screenwhich is roughly six times the normal computer or monitor screen area isutilized to provide enhanced image viewing quality and resolution, andthe ability for multiple physicians to collaborate without having to“crowd around” a smaller display. The images displayed may also benetworked to other local or remote devices if desired, using for exampleconventional data networking techniques, to allow for multi-uservisualization.

It will also be recognized that separate display devices, whether singleor multi-portioned, can be used to evaluate data from one or moresubjects contemporaneously.

The foregoing approach capitalizes on the innate human capability forsubstantially parallel or multiplexed image processing within the brain,especially where the subject matter of the multiple parallel/multiplexedimages is substantially similar and the changes occurring in the imagesare not complex or rapid. Consider the limiting example of several(e.g., six) similar images of different blades of grass projected incorresponding portions of a display screen; an average human being can“scan” these six images using periodic eye movement to detect changes inthe images (such as changes in coloration, movement, or shape/size),without having to intently focus on one image at a time, or bytime-multiplexing the images to the brain. In this example, the rate ofnew information introduction into the eye (and brain) of the viewer isquite slow; hence, to watch each sequence sequentially (i.e., watch eachblade of grass grow, followed by the next, and so forth) woulddramatically underutilize the capabilities of the brain, and comprise asignificant waste of time. Conversely, images of six fast-paced actionmovies projected contemporaneously on a screen would on average greatlyovertax the abilities of the viewer's brain, thereby causing significantloss of information. The viewing of multiple images of an intestinalprobe moving through the intestine of a human considered to be closer tothe former (grass) paradigm than the latter, since the movement of theprobe through the intestine via peristaltic action is comparativelyslow, and the subject matter does not vary significantly (i.e.,different portions of the intestine are generally somewhat similar).

Human peripheral vision (i.e., that outside the area of direct focus ofthe eye) is also advantageously adapted to detect movement and changes,which is used by the present invention to some degree to allow aphysician to monitor a plurality of regions of the intestine in parallelfor changes or physiologic features of interest (i.e., disease).

It will also be appreciated that the update of the display portions 3511of the present invention may be made discrete as opposed to continuousin nature; i.e., the sequence of images may be non-continuous orcomprise “snapshots” of data obtained from the probe. The sequenceand/or timing of the images displayed in one portion 3511 may also becoordinated with those of one or more other portions of the screen 3510,so as to minimize the opportunity for lost or non-viewed data. Forexample, wherein a row-and-column display is used (e.g., two rows ofthree portions 3511 each), the display interval can be staggered suchthat an image will change or “flip” at a predetermined interval afterthe change in the prior portion 3511, thereby creating a ripple effectacross the screen in row- and column order. Hence, the physician orother user can coordinate their eye movement to scan each portion justafter it changes, thereby in effect creating a loop wherein thephysician can jump portion-to-portion with their eyes to view the nextchanging frame.

In terms of data efficiency, consider the exemplary embodiment wherein afour-hour total length (L) data stream in real time is divided into sixforty-minute segments as previously discussed. If each segment issampled once every period t and updates its display portion at apredetermined rate, then the desired level of image compression can beachieved by adjusting the sampling and display rates accordingly. Hence,if the program samples data from each of the six segments at a rate ofone “frame” every six seconds, and then displays each sampled frame inits respective portion 3511 on a staggered basis for one second beforethe next portion is updated, an overall display update rate of once persix seconds is established. Accordingly, the algorithm samples a givesegment for a screen portion once every six seconds, and displays thesampled image for six seconds, until it is time to again sample thesegment for that portion. The effect is to permit viewing of all sixsegments as previously described (i.e., 6:1 compression), yet with theuser only viewing one portion 3511 at a time on a rotating basis ascompared to simultaneously running segments in the prior embodiment.

If greater compression is desired, the display update rate and/orsampling rate can be adjusted. For example, if an update rate of onceevery ½ second is chosen, then each portion will be updated every threeseconds. If the displayed data is sampled once every six seconds ofsegment data as before, yet displayed once every three seconds, then thealgorithm(s) must “fast forward” each segment by three seconds duringeach interval in order to present a snapshot at three second intervalsof data taken once every six seconds. Stated differently, the user ispresented with a “snapshot” from each segment taken six seconds apart(in data space) every three seconds (in display space). Likewise, lowercompression can be afforded by increasing the sampling rate above thedisplay rate, thereby either lengthening the total runtime for eachsegment beyond that associated with real-time running of 6:1 compression(i.e., 40 minutes in the present example), or alternatively allowing thesoftware to “drop” every other sampled frame. Myriad other permutationsof data rate/sampling rate/compression ratio may be used consistent withthe invention.

In another embodiment of the invention, the system 3500 may be coupledto a headset (not shown) worn by the physician which is adapted to scanthe retina or other portion of the physician's eye(s) using incident orreflected energy to determine where the physician is looking as afunction of time relative to the headset's coordinate system. As thephysician moves their eye(s) to look at another portion 3511 of thescreen 3510 (or alternatively fails to move their eyes for a prescribedperiod of time), the signal processing associated with the reflectedenergy determines the portion 3511 of the screen 3510 at which thephysician is looking, and performs the desired function. Hence, wheresomething in an image displayed in a given portion 3511 of the screen3510 captures the physician's attention, the algorithm can detect thisinterest and perform one or more desired functions relating to the datadisplayed in that portion, such as zooming, fast-forwarding,slow-motion, tagging of data for later examination, updating (if thenon-continuous embodiment of the invention is utilized), etc. Theretinal device is also optionally used to trigger software generation ofpull-down menus or pop-up windows on the screen 3501, allowing the userto coordinate selection via an input device 3509 (or via speech,described below) with their eye movement in order to effect selectionfrom the menu.

Various embodiments of optical scan technology are known in the priorart, including for example the infrared (IR) that developed by CAEElectronics Ltd. of Montreal, Canada. The CAE eye-tracking device canrecord and analyze accurately up to 500 eye positions per second, andworks by capturing and processing the reflections of a low-level beam ofinfrared light shone onto the eye. Multi-element arrays capture theimage of the eye and digitize the information, which is then processedin real time by a fast, dedicated signal processing unit. The differencein position between the light reflected by the pupil reveals theinstantaneous direction of user gaze. Yet other methods for determiningthe direction of a subject's gaze relative to a fixed point or region inspace are well known in the art, and accordingly not described herein.See, e.g., U.S. Pat. No. 6,394,602 entitled “Eye tracking system” issuedMay 28, 2002, U.S. Pat. No. 6,154,321 entitled “Virtual retinal displaywith eye tracking” issued Nov. 28, 2000 and U.S. Pat. No. 5,712,684entitled “Viewing apparatus with visual axis detector” issued Jan. 27,1998, each of which are incorporated herein by reference in theirentirety.

Alternatively, a prismatic “HUD” (Head-up display) of the type wellknown in the art may be substituted in the aforementioned headset forthe retinal scan technology. Specifically, a miniature screen or prismdisposed in front of one eye of the subject via the suspension mechanism(e.g., arm) of the headset receives optical signals for display to theuser. Such devices are disclosed in, inter alia, U.S. Pat. Nos.6,222,677 entitled “Compact optical system for use in virtual displayapplications” issued Apr. 24, 2001, and 5,943,171 entitled “Head mounteddisplays using reflection light valves” issued Aug. 24, 1999, both ofwhich are assigned to IBM Corporation and incorporated herein byreference in their entirety. For example, in one variant, thehead-mounted display is used to display option menus to the user, suchas GUI pull-down menus from which the user may select using one or moreinput devices (including speech commands as described subsequentlyherein).

Furthermore, it will be recognized that speech recognition technology ofthe type well known in the art may be used consistent with the presentinvention. Software and audio apparatus (microphone, etc.) adapted torecognize the voice commands of a user and translate them into actionsrelating to the system 3500 is used in one embodiment to facilitate moreefficient viewing. For example, a user voice command of “Zoom in 2×,Zone 3” would be interpreted by the system processor 3502 andaccordingly cause the display of the segment contained in a particularportion 3511 of the display 3510 to be enlarged or increased in scale bya factor of 2. This functionality may also be coupled with the opticaldirection apparatus previously described, thereby simplifying the verbalcommand syntax by providing spatial context to the commands. Hence,using such apparatus, the user would state “Zoom in, 2×” while lookingat Zone 3 on the display, the software being adapted to recognize thatthe verbal command was given in the context of the “viewed” zone at thatpoint in time. Similarly, if multiple displays 3510 are being viewedsimultaneously, the optical apparatus provides spatial context asbetween the multiple displays.

The speech recognition apparatus of the present invention includes ahigh quality, high SNR audio microphone, analog-to-digital converter(ADC), and linear predictive coding (LPC)-based spectral analysisalgorithm run on the system digital signal processor. It will berecognized that other forms of spectral analysis, such as MFCC (MeIFrequency Cepstral Coefficients) or cochlea modeling, may be used.Phoneme/word recognition in the present embodiment is based on HMM(hidden Markov modeling), although other processes such as, withoutlimitation, DTW (Dynamic Time Warping) or NNs (Neural Networks) may beused. Myriad speech recognition systems and algorithms are commerciallyavailable (such as for example those offered by IBM Corporation orScansoft Inc.), all considered within the scope of the inventiondisclosed herein.

In yet another embodiment of the invention, the foregoing display 3510is divided into a plurality of portions 3511 based not on the segmentsof the data stream of a single subject, but rather the data streams oftwo or more subjects. For example, the physician may desire to aggregatethe data from six separate patients onto the aforementioned six-portiondisplay 3510, such that instead of viewing the nominal four-hour datastream from a single patient as with the prior art, he/she can view datafor six patients simultaneously during the same four hour period,thereby again providing 6:1 compression, and reducing the time spent perpatient from four hours to forty minutes. This approach has the benefitof allowing viewing of generally comparable portions of the intestinaltract of the various patients simultaneously, thereby offering thephysician with some level of comparative visual data by which to analyzea specific patient's data. Alternatively, data from a “normal” orcontrol intestine may be inserted into one of the portions 3511 ifdesired for such purposes.

Where the various individual data sets are different in total length L,the algorithm is adapted to optionally expand or compress the data foreach patient so as to make the various data coextensive in time. Hence,in effect, the system 3500 adjusts the viewing speed of each stream atstart-up (or during operation) so as to have all segments start and stopat the same point in time, thereby maximizing physician efficiency. Suchadjustments may also be dynamic during operation, such that if forexample the physician pauses one data stream part-way through for closerexamination, the speed of display of that stream after removing thepause condition is accelerated based on an extrapolation of remainingrun time as compared to those for the other segments, such that(assuming no further pauses), the viewing of various streams will becompleted at the same time.

Alternatively, the speed of display of the remaining (i.e., non-paused)segments may be slowed, such that approximately coincident completion isagain achieved, yet with longer overall duration. This approach may bedesirable where the paused segment shows disease or other problematicconditions warranting a closer, slower inspection. For example, if thephysician pauses a segment associated with a given patient, and upondiscovering signs of disease, releases the pauses in favor of a slow orreduced rate of display (i.e., slow motion forward), the data streamsfor the other patients may be proportionately adjusted by the algorithmto preserve the common termination time if desired. In this fashion, thephysician can place the entire display (i.e., all n portions) in slowmotion.

Furthermore, upper and/or lower “speed limits” may be placed on thesystem 3500 via the algorithm, such as by user entry of data via astart-up or configuration menu of the type well known in the art, or viapull-down menu or similar GUI. Such speed limits may act as artificialboundaries to the speeding up or slowing down of data at start-up ordynamically as previously described. Hence, for example, where the datasegments for the various subjects are very different in length, theupper speed limit may act to control the degree of display rate increasefor a segment undergoing temporal compression so as to avoid thephysician “missing” data. If it is known that a given value for thedisplay rate of the data is the maximum upper limit for reliablediagnosis, then any attempts by the system's algorithm to increase thedisplay rate of a given segment above that maximum prescribed rate inorder to compress the run-time of the segment will be frustrated by theupper speed limit. Accordingly, at that point, the system 3500 willoffer the user (via, e.g., interactive menus or windows) the option ofslowing down the other segments as necessary to provide coincident datatermination, or alternatively just letting the other segments complete“earlier”, thereby allowing the physician to focus more effort on theremaining (running) segments after such termination of the othersegments.

In practical use, there is little real danger afforded by running a datastream's screen display rate too low; however, the low speed limit ofthe present invention can be used to, inter alia, prevent the user orphysician from inadvertently extending the duration of one or moresegments beyond that desired, or missing motion-related artifact (e.g.,pulsations of tissue, severe jars to the patient, etc.) which can bebest visually detected at a minimum display rate or greater.

In yet another embodiment, the apparatus 3500 of the invention isadapted to select and display only designated portions of the datastream generated by one or more probes. Specifically, in one variant,the system software is adapted to select frames of data at pre-selectedintervals regularly spaced along the duration of the data stream, ineffect forming a series of snapshots for the physician to view. Each ofthe selected frames are stored in a data buffer associated with thesystem; e.g., a FIFO buffer memory of the type well known in the dataprocessing arts, or other types of storage scheme such as virtual memoryon the system hard drive, etc. The frames are also stored with one ormore data fields associated with each, the data fields being used in thepresent embodiment as absolute or relative pointers to other locationsin the data stream. In one variant, the data stream protocol comprises asequence of uniform data packets, a group of packets in the aggregatecomprising a frame and being assigned a sequence number. Each of theframes selected by the system software for display to the user is storedin the data buffer along with its sequence number, the latter being usedto index the frame with respect to other frames in the stream so as topermit the user to “grab” frames for subsequent closer inspection.Hence, in the instant embodiment, the user views a series of framesrepresenting only discrete portions of the total data stream (e.g.,every sixth frame or container of data), and is able via softwarecommands to select individual ones of the displayed frames forsubsequent evaluation. The selected frames are stored in the data bufferalong with a sequence or index, thereby allowing the user to (i)identify the relative timing of multiple frames selected, and (ii)select portions of the data stream for complete viewing. FIG. 35 billustrates an exemplary packet protocol useful with the invention.

Specifically, the index number can be used to display to the user therelative timing or sequence of the multiple frames selected that theyare viewing. Alternatively, a time stamp can be used for each selectedframe to display the relative timing of frame with respect to the totalduration of the data stream. For example, where six frames of data areselected, six different time stamps (or indexes) will be displayed tothe user so as to indicate which frame came first, second, and so forth.This index or time stamp information is also used to sequentially orderthe selected frames in lineal order on the display screen 3510.

Furthermore, the index or time stamp can be used as the basis forretrieving selected portions of the data stream as specified by theuser. For example, in one embodiment, the system software provides theuser with menu or “right click” capability via the input device toselect various options for expanded viewing of one or more frames. Wherea selected frame displays data of possible interest, the user simplyselects the appropriate pull-down menu or right-clicks the mouse, whileselecting the screen portion 3511 or window of interest, and selects oneof the options allowing for viewing of the data contiguous with theselected frame. The index/time stamp is accessed by the software basedon the user's selection, and used as the seed for the calculations toidentify stream data for retrieval. In one embodiment, the frames oraggregation of packets are a known temporal duration, as is the totallength of the data stream, and hence the user selection of a givenperiod of time for viewing with respect to the indexed/stamped frame ofinterest is used to determine the number of packets to be retrievedrelative to the selected frame. The user is further able, via theaforementioned user interfaces, to select the relative temporal positionof the selected frame to the retrieved data, such as for example byselecting “+5 min.” on the menu. This command assigns the originallyselected frame as the temporal or index starting point for dataretrieval, with the equivalent of 5 min. of subsequent data retrievedfrom the stored stream and displayed to the user as a video “clip”.Alternatively, the user may select the option “+/−5 min.” from the menu,wherein the system software designates the selected frame as the centerpoint of the data retrieval, and accordingly retrieves data equivalentto 5 min. before the reference frame, and 5 min. after, and displays thedata again as one continuous clip. Alternatively, the user can selectvia menu to zoom in on the selected frame. As can be appreciated bythose of ordinary skill, myriad other options for data manipulation,selection and display are possible consistent with the invention, theforegoing being merely exemplary of the broader concepts.

Other embodiments of the invention permit the selection of data framesbased on criteria other than periodicity, including for example thefollowing:

(i) User pre-selection—The selection of frames may be based on inputsobtained from the user before or at the time of viewing, such as theselection of points along a graphical or other depiction of a timelinerepresentative of the entire length of the data stream (e.g., bydividing the data stream into n segments of the same or differentlength, and then sampling at the segment boundaries).

(ii) External inputs—The selection of frames may be based on one or moreexternal inputs, such as data corresponding to one or more actualphysical locations of the probe generating the data within the subject'sintestine during passage. For example, where the probe is tracked duringits progression through the intestine by ultrasound, RF energy,X-ray/CAT scan, MRI, or the like, data obtained from such trackingmethods may be correlated to temporal coordinates in the data stream.This approach may be useful, for example, where the subject complains ofpain or discomfort in one or more given locations of the intestine; thephysician can decide to selectively view the portions of the data streamrelating to the probe being disposed at or near these locations. Suchcorrelation can be accomplished using any number of methods, such asartificially inserting a time stamp into the system 3500 via theGUIs/input device 3509 when the location of the probe is known tophysically coincide with the location of the subject's discomfort, etc.

(iii) Autofluorescence data—Portions of the data stream may be selectedby the user based on data relating to autofluorescence analysis(described above). Specifically, the probe may be configured andoperated such that the autofluorescence analysis is conducted atperiodic intervals during the traversal of the probe through theintestine, as specified by a sampling ratio R. For example, theautofluorescence diode and array may be activated once per minute oftravel for a duration of t seconds (R=60/t) so as to obtain a series ofperiodic “snapshots” of the auto-fluorescent signature of the tissue inthe intestine proximate the probe. This data is transmitted off-probealong with the visual data (such as via time-division multiplexing(TDM), FDM or sideband transmission, or other technique), such that thesystem 3500 has both sets of data available for viewing by thephysician. Alternatively, the probe (or different probes) can be sentdown the intestine multiple times to collect the various data. Theautofluorescence data stream can then be previewed by the physicianeither manually, such as via a visual display of the data in sequentialor mosaic form as previously described herein, or alternatively viaanother technique such as software processing of the data. Such softwareprocessing may comprise, for example, analyzing the “snapshot” frames ofautofluorescence data for changes in the remitted energy spectrum as afunction of time (e.g., versus prior data obtained for the same patient,whether in the current traversal or one or more prior thereto), oragainst empirical data derived from other patients, or even against anestablished criterion such as a threshold remittance intensity. Forexample, the integrated area under each remittance spectrum may becalculated in order to compare different spectra. Alternatively, thenormalized magnitude of the remittance intensity peak may be computedfor comparison. As yet another alternative, the spectral location (i.e.,wavelength λ or frequency f) of the peak in the remittance spectra maybe compared in order to identify shifts or variations potentiallyrelating to disease. Myriad techniques for analyzing spectra for shape,artifacts and/or changes may be used consistent with the presentinvention, such techniques being well known to those of ordinary skillin the mathematical and experimental arts.

When the physician has identified one or more regions of interest withinthe subject's intestine (corresponding to one or more of the periodicautofluorescence frames), they simply select the frames of interest viathe system 3500, such as via GUI menu or input device. The systemsoftware of the instant embodiment is programmed to correlate the timestamp associated with each frame selected to the appropriate portion ofthe visual data stream, and select and buffer data from the visualstream within prescribed temporal coordinates of the selected frame(s).For example, where the physician selects two frames of autofluorescencedata and requests (via the user interfaces previously described herein)the viewing of +/−5 minutes of data on either side of the frame, thesystem software obtains the time stamps of the selected autofluorescenceframes, locates the corresponding point(s) within the visual datastream, and then selects +/−5 min. of data for each (for a total of 20min. of visual data in the present example). Hence, rather than watchseveral hours of data in a contiguous stream, thereby potentiallyfatiguing the physician and detracting from the cost efficiency of thediagnosis, the present embodiment of the invention allows the viewer topreview the entire visual data stream based on a series ofautofluorescence snapshots, and then focus in on the regions of interestwithin the visual data stream accordingly, thereby greatly enhancing thecost efficiency and quality of the diagnostic process.

(iv) Antigen/chemical detection—As previously discussed, one embodimentof the probe of the present invention is adapted to detect one or moreantigens within the intestinal tract, and provide a signal (or data) tothe system so as to alert the operator to the presence of theantigen(s). Accordingly, the system 3500 of FIG. 35 may be configured totime stamp such antigen detections, and use this time stamp informationas the basis for expanded viewing by the physician. For example, thephysician may preview the entire visual data stream for correspondingantigen or chemical detection events, and select portions of the visualdata relating to these events for examination in much the same way theautofluorescence data time stamps were used as described above. Hence,if the physician is screening the patient based on narrowly focusedcriteria, such as the presence (“go/no-go” test) of a particularcondition or disease with no other ancillary screening, the physiciancan efficiently locate the potentially relevant portions of the visualdata stream based on the presence of one or more “markers”.

While specifically described herein with respect to antigen/chemicaldetection and autofluorescence data, it will be appreciated that thisconcept (i.e., the use of a narrowly focused screening criterion, suchas a “go/no-go” test) may be applied more broadly to most any type ofevent occurring contemporaneously with the collection of visual data,and/or even those artifacts present in the visual data alone which areindicative of the potential for conditions warranting increasedscrutiny.

(v) External prior data—Similarly, the system 3500 may be adapted to useprior existing data and/or inputs as a means of targeting the selectedacquisition of data from the patient during probe traversal. Forexample, data relating to procedures or inspections such as priorendoscopic, CAT scan, or MRI analyses can be analyzed in order togenerate windowing criteria used during probe traversal. Consider thesimple yet exemplary case wherein a prior upper GI series of the subjectyields information indicating that portions of the small intestine maybe ulcerated or perforated. Knowing the rate of traversal of the probethrough the subject's upper GI tract (which may be selected from adatabase of empirical data, or entered by the user via GUI or otherinput prior to probe introduction in the patient), the probe can beprogrammed to collect data only during prescribed “windows” specified bythe system software and corresponding to the approximate locations ofthe disease, thereby, inter alia, minimizing the amount of potentiallyextraneous data obtained by the probe. It will also be recognized thatsuch windowing or blanking need not necessarily be tied to any specificprior or contemporaneous event, but rather may alternatively beprogrammed into the system 3500 for any reason. For example, where thephysician wishes to examine only a portion of the intestinal tract, suchas to limit their potential malpractice liability for inspections ofareas of the intestine not conducted, they may configure the probeand/or system 3500 as applicable (i.e., either by shutting the probeoff, or simply dumping data streamed from the probe at the system 3500)to capture data only during the relevant potions, such as just for thesmall intestine, etc.

In this fashion, the system 3500 can also be controlled and made legallycomparable to other prior art technologies (such as the fiber-opticendoscope) which have only limited reach into the intestinal tract.Stated differently, the diagnosing physician can avoid legal malpracticeissues relating to non-diagnosis of or failure to identify conditionsoccurring in non-considered regions of the intestinal tract by in effectswitching off the data corresponding to that non-diagnosed portion. Aswill be recognized by those of ordinary skill, the system 600 mayfurther be equipped with verification and audit capability in thisregard, such that a printed and/or electronic record of the datacollection process and times (such as via data time-stamping) ispreserved for future use. A digital watermark or signature of the typewell known in the encryption and security arts may be employed to thisend in order to authenticate data for later use, such as during legalproceedings. Additionally, a network interface may be used, wherein thesystem 3500 transmits one or more authentication data packets (e.g.,containing the viewed portion of the data stream, and/or the temporalwindow specifications of the session) to a third party facility adaptedto receive, store, and authenticate the data for later use, much as anelectronic transfer of funds is conducted within the financial industry.Myriad other techniques for guaranteeing the authenticity of priorcollected data are available and may be used with the present invention.

Similarly, the data rate of the system 3500 may be adjusted during oneor more temporal windows so as to accelerate the viewing of data duringperiods corresponding to portions of the intestinal tract having a lowerprobability of disease. For example, where a given patient has recentlyundergone a colonoscopy with no identified disease or problems in thatregion, the probability of disease occurring in that region in theinterim since the colonoscopy is very low. Hence, the physician maydecide to “fast forward” that portion of the data stream correspondingto the colon. This fast-forwarding is accomplished in one exemplaryembodiment through the system display software, which increases the datadisplay rate on the display device 3510 according to a pre-selectedcompression ratio, thereby effectively compressing the time needed tocomplete that segment of the data stream.

Hence, if desired, the operation of the system 3500, and specificallyits software and which data stream frames are displayed to the user, mayadvantageously be coupled to events occurring before, contemporaneouslywith, and/or after the collection of data via the probe. In thisfashion, the comparatively large amount of data collected by the probeduring a normal traversal of the intestine can be intelligently reducedand screened based on other data or information available to thephysician. These events may be intra-probe (e.g., antigen detection,ultrasound detection, coupled to the in situ power-up of the probe orreceipt of an external signal; etc.), or external to the probe (e.g.,data derived from other tests or external analysis of data derived fromthe probe, based on the user's input, etc.) as will be appreciated bythose of ordinary skill.

Image Recognition

In yet another embodiment of the invention, the software of the system3500 is configured to perform analysis of the data obtained by the probeoptical band sensor (e.g., CCD or CMOS array) so as to automaticallyidentify one or more artifacts or features contained therein.Specifically, in one exemplary configuration, the software includesalgorithms adapted for feature recognition based on pre-stored datacontained within the system 3500. These algorithms have commonalitieswith two prior art technologies, namely 1) DSMAC (digital scene matchingarea correlation) as used on, inter alia, the Raytheon BGM-109“Tomahawk” cruise missile; and 2) facial recognition software currentlybeing used with respect to the identification of terrorists and othercriminals, such as the FaceIt® ARGUS software offered by IdentixCorporation.

As is well known, the DSMAC technology utilizes digitized imagesobtained from an optical, electro-optic (EO) or IR sensor disposedwithin the parent platform as the basis for comparison to pre-stored“images” of targets, the latter obtained from, for example, low-earthorbit optical or IR satellites. Since the missile may attack suchtargets from various attitudes, mathematical manipulations of dataobtained via the input sensor are conducted in essentially real time inorder to align the image or convert it to the desired perspective, andextract features which are then correlated to similar features withinthe pre-stored data. This feature may be used, for example, in theterminal guidance phase of the missile, in order to validate the targetbefore activation and delivery of the missile's munitions. See, forexample, the techniques described in U.S. Pat. Nos. 4,925,274 entitled“Correlation Techniques” issued May 15, 1990, 4,802,757 entitled “Systemfor determining the attitude of a moving imaging sensor platform or thelike” issued Feb. 7, 1989, 5,146,228 entitled “Coherent correlationaddition for increasing match information in scene matching navigationsystems” issued Sep. 8, 1992, and 5,173,949 entitled “Confirmed boundarypattern matching” issued Dec. 22, 1992, all of which are incorporated byreference herein in their entirety.

Facial recognition software such as ARGUS utilizes a generally analogoustechnique, of image digitization, wherein certain facial features areidentified and evaluated for a plurality of individuals (such as thepatrons of a football game) passing in proximity to the sensor(s), andthen subsequently compared to pre-stored data in order to attempt tomatch the in situ data to one or more entries within the pre-storeddata, thereby in effect identifying the individual. Images captured ofthe individual are first scanned to localize the region of interest,then these regions are analyzed (including, for example, alignment andnormalization of the image) to measure a plurality of physical featuresassociated with the face of the individual being evaluated. See, e.g.,U.S. Pat. No. 6,108,437 entitled “Face recognition apparatus, method,system and computer readable medium thereof” issued Aug. 22, 2000, alsoincorporated herein by reference in its entirety.

Both of the foregoing technologies are generally speaking quitecomputationally intensive, requiring significant MIPS for even routinecorrelation and identification tasks. With the advent of ultra-highspeed digital processors (such as the aforementioned MotorolaMSC8101/8102 series devices, or the Texas Instruments TMS320C6x or C80DSPs), such processing can presently be conducted in real time or nearreal time. However, it is desirable to reduce the computationrequirements of such analysis, thereby permitting yet faster evaluation.

With this backdrop, an exemplary embodiment of the present invention isnow described with respect to FIGS. 36 a-36 f.

As previously discussed, the probe of the invention is adapted togenerate a stream of data (either via real-time off probe transmission,or via delayed readback from a storage device) relating to visual imagesobtained within the subject's intestine. This data is processed by thesoftware disposed on the monitoring system 3500 which, in the instantembodiment, is adapted to analyze the visual data stream for one or moreartifacts or features. As used herein, the term “visual” refers to anyportion of the electromagnetic spectrum which may be perceived by asensor, including the IR and UV portions as well as the visual region.

As described above, packets or aggregations of data in the visual datastream are packaged into data frames of predetermined length in bytes ortemporal duration, for additional processing. In the present context,such additional processing comprises analysis of the frames viaalgorithms running on the system processor(s) 3502 for specific featuresor artifacts relating to known diseases or conditions within theintestine. For example, the formation of intestinal polyps is welldocumented and readily observed through visual endoscopic analysis underthe prior art. Such polyps generally have a characteristic shape; i.e.,the formation of a protrusion or projection 3604 from the wall of theintestine 3602 as shown best in FIG. 36 a. Hence, the visual-band imageobtained via a sensor approaching a polyp within the intestine from the“upstream” side would generally contain (i) a curved and substantiallyconsistent feature 3610 representing the wall of the intestine, and (ii)a projection 3604 punctuating the curved feature 3610, as shown in FIG.36 a.

Similarly, a normally shaped intestine when viewed by such sensor wouldappear as in FIG. 36 b, with an aperture 3620 of appreciable size formedgenerally near the center of a “band” of lighter colored tissue 3622. Incontrast, an occluded or distended intestine (FIG. 36 c) would appear tohave an irregularly-shaped aperture 3624 and/or a reduced area of theaperture (i.e., larger ratio of light-colored or reflective tissue areato aperture area).

Numerous other types of maladies or diseases associated with theintestinal tract can be similarly characterized by features or artifactswithin their visual images, including without limitation variousdifferent types of polyps, diverticulitis, occlusions/adhesions,carcinomas, and ulcerations.

Accordingly, the present invention capitalizes on the foregoing abilityto visually characterize conditions of the intestine coupled with theefficiency of digital data processing in order to provide the physicianwith a substantially automated process for screening data obtained fromthe probe for such features or artifacts. In the illustrated embodiment,each type of known feature or artifact associated with one or morediseases or conditions is to some degree unique (much as the human faceor the target facility) and can be characterized in terms of a number ofnodal points. Using the signal processing power of the aforementionedDSPs, the database of such diseases used with the present invention canadvantageously be expanded to a large number of different “template”images, the latter being used as the basis for comparison andidentification.

It will be recognized that while the following discussion is cast interms of the aforementioned polyp in the context of visual band imagedata, the method is generally applicable to a broad range of artifactsand conditions occurring within the intestine, as well as to otherranges of electromagnetic radiation (e.g., IR) and even acoustic energywith sufficiently high frequency.

In the illustrated embodiment, eight (8) nodal points 3627 are assignedon the feature of interest, as best shown in FIG. 36 d. Obviously, moreor less and/or different nodal points may be used consistent with theinvention. These nodal points are discrete locations on the image framewhich the software assigns based on, inter alia, decomposition of theframe into a plurality of pixels or image segments, each having its owndiscrete properties, and subsequent mathematical analysis. Specifically,the instant embodiment (i) first identifies the feature boundariesthrough analysis of the intensity of pixels processed according to apixel map; (ii) performs mathematical curve-fitting to the pixelsidentified as being part of the boundary as shown in FIG. 36 e, and then(ii) selects the nodal points used to characterize the feature based onthese mathematical functions. In the present embodiment, the entirefield of view (FOV) of the frame is used as the basis for analysis sinceit is spatially small, and the features generally comprise a significantfraction of the FOV. However, the FOV may be reduced if desired, much asthe aforementioned face recognition technology of the prior art firstidentifies the facial region of an image of a person as being the“region of interest” before performing the facial recognitioncomputations. A multi-scale algorithm of the type well known in thefacial recognition software arts may optionally be used for scanningimage frames for features or artifacts which are not in the immediatefocal region of the sensor, with any such identified features then beingidentified for further analysis as described below.

In the instant embodiment, image processing of each pixel in the FOV ofinterest is accomplished on the basis of pixel intensity (or “pixelgrayscale value”), measured as an absolute value independent of imagedepth (or alternatively as a relative value with respect to other pixelsin the image). Hence, the polyp boundary 3625 shown in FIG. 36 d isfirst discerned via analysis of the pixel matrix based on intensity,specifically a multi-bit binary digital value representing the intensityof that pixel. Higher intensity indicates light-reflective tissue closerto the sensor, while lower intensity pixels are correlated to moredistant tissue (or no tissue). Feature boundaries are determined fromthese intensity values according to well-known algorithms not describedfurther herein.

As will be recognized by those of ordinary skill in the image processingarts, the image depth of the data (i.e., the number of bytes per pixel,roughly correlated to the “richness” of the image) obtained from thedata stream may be adjusted in order to provide desired attributes fordata filtering and analysis, whether on-probe or off. Furthermore, colorimages (e.g., wherein each pixel carries data relating to the respectiveR-G-B intensities, or a “fake” color index assigned by grayscale coding)may be used as the basis for feature analysis.

The instant embodiment of the present invention also capitalizes on theobservation that there are only a limited number of possibleorientations for features within the intestinal tract. Specifically, allfeatures or artifacts of interest occurring within the intestine areoriented or in some way related to the interior surface of theintestine, modeled herein as a substantially cylindrical tube disposedsubstantially co-axially with the longitudinal axis of the sensor of theprobe. Furthermore, at least portions of most features of interest willbe disposed transverse within the intestine, since the substantiallycircular FOV of the probe sensor intersects the cylindrical intestineinterior wall as a radial circle or band. These assumptions, coupledwith the use of ratios versus absolute measurements, greatly simplifythe image processing and recognition algorithms, since no determinationof size (i.e., how large the feature is in absolute terms) or alignment(i.e., how the feature is aligned relative to the sensor) or imagenormalization is required, as is required in other software approaches.

As a simple example, the feature boundary 3625 of the foregoing polypcan be simply modeled in a template as a semi-circle of different radiusintersecting with two linear functions. For comparison between thetemplate and an actual in situ image, the system 3500 need not know theorientation of the template feature or the actual feature, but ratheronly their parameter ratios. The orientation is not needed since thepolyp, regardless of orientation, will always have one portioncontacting the inner intestinal wall (cylinder), and will always presenta cross-sectional area to the FOV of the sensor. In many cases, the backside of the polyp looks similar to the front, and the side. Also, in thecylindrical coordinate system (r, Φ, Z) of the intestine/probe,information regarding the azimuthal disposition of a feature (i.e.,where on the circumference of the intestine the feature is located) isgenerally not needed, since only the recognition of the shape is ofsignificance, and not its relative angular displacement. Contrast theface in the face recognition system, wherein (i) the subject's head doesnot always present a “useable” cross-section (such as if the face isturned away or looking down), and (ii) the aspect or alignment of theface is critical, since the parameters being measured are unique to oneaspect.

The algorithm of the system software next performs curve-fitting (eitherpiece-wise or continuous, as appropriate) to assign a mathematicalfunction to each portion of the feature boundary. Algorithms formathematical curve fitting are well known in the software arts, andaccordingly not described further herein. These functions are next used,in the context of a relative coordinate system assigned to the imagedata by the curve-fitting software, to characterize the feature (polyp)in terms of the eight aforementioned nodal points, as shown in FIG. 36e. Specifically, the feature maximum width 3627, height 3629, and basewidth 3631 are determined through analysis (such as local maxima/minimaidentification etc.) of the determined functions. In the illustratedexample, the salient portions of the polyp feature 3604 can be modeledas two circular functions (form of x²+y²=r²) of different radius, andtwo linear functions of the form y=mx+b, the former two intersecting thelatter two. These functions are then analyzed for example based on (i)the diametric point of the first circular function (width 3627), (ii)the maximum distance between first and second circular functions (height3629), and (iii) the distance between the points of intersection of thetwo linear functions and the second circular function (base width 3631).

It will further be recognized that the component functions generatedduring curve-fitting may be used as the basis for feature identificationas well. Specifically, the functions comprising the feature boundary maythemselves be descriptive of the feature. As a simple example, considera cube which, regardless of aspect or attitude, will never have a curvedfeature boundary. More sophisticated analysis of the types,intersections, and curvatures associated with a given feature may alsobe employed. In the case of the exemplary polyp previously described,the relative positions and compositions of the various mathematicalfunctions used to generate the boundary (i.e., two semi-circles ofdifferent radius intersecting two linear functions) are descriptive offeature. Hence, the software of the system 3500 may be configured tosearch the “feature database” based on feature constituent functions.Similarly, the feature templates may be constructed so as to includethis information, along with or in place of the parametric ratios.

The parameters derived from the foregoing feature analysis are stored asa multi-byte feature descriptor packet 3670 (FIG. 36 f) which uniquelyidentifies the feature in terms of the foregoing parameters, as well asthe time stamp associated with the frame under analysis. This packet isstored in a designated storage location or held in buffer memory forlater retrieval, such as for use in the previously described-“mosaic”display mode.

Relevant portions of the descriptor packet (i.e., the data correspondingto feature characteristics) may also be compared to pre-stored templatesor models in order to assist in classification of the feature.Specifically, since the system has no a priori knowledge that thefeature in question is a polyp, or what type of polyp, it can beconfigured to attempt to match the subject feature to one stored in thesystem database. For example, the system may store a plurality ofparadigms or templates for polyps that have different maximal width,base width, and height ratios, dependent on the type of polyp (e.g.,sessile, pendunculated, carcinoma neoplasm, etc.). In the presentcontext, these are known as “thin” templates since they only includeparametric ratio information (or constituent function information). Thealgorithm accordingly calculates the ratios for the subject feature(e.g., maximal width to height, height to base width, etc.) and comparesthese relative ratios to those stored previously within the system, andscores the subject feature against the stored templates using any numberof well known data comparison and scoring techniques well known in theart, including for example least squares. A probability or “score” isthen generated for use, inter alia, by the user. For example, a typicalscreen display would comprise a table having the feature time stamp, andthe scores or probabilities for each type of pre-stored featurecontained therein. Myriad other display formats may be used.

Additionally, templates may be generated based on images obtained, forexample, from the probe itself (or another like it), an endoscopicdevice with camera or other imaging apparatus attached, or may even beartificially generated such as via a computer program. Such templatesare considered “fat” in that they contain not only the processedparametric ratio data and or constituent feature information, but alsothe underlying image data from which the template was derived. Adatabase or library of templates (thin and/or fat) may be madeaccessible via LAN, WAN, interne, or other resources (such asdistributed CD-ROM), with corresponding feature definitions in much thesame way that computer virus definitions are periodically updated by auser of a standard PC. In this fashion, the user of the presentinvention can make use of images gathered by other physicianscorresponding to known conditions or diseases, either in directvisualization (i.e., by displaying the in situ feature contemporaneouslywith the template image), or by the parametric data, or both.

The templates may also be annotated with one or more bytes ofinformation (text, notes, etc.) providing background or explanatoryinformation associated with each template in order to assist othersusing the template in diagnosis of their patient. For example, it may beuseful to know the age, sex, ethnicity, stage of progression of thedisease, and brief treatment history for the subject from which thetemplate (image) was obtained. Such information can be read by thesystem processor 3502 from the template description field(s) in thepacket (not shown) and displayed on the display device 3510, printedout, or otherwise accessed by the user.

The use of ratios in the instant embodiment advantageously allowscomparison of data on a relative footing, thereby obviating the need forany sort of absolute distance measurement, alignmentanalysis/correction, or calibration, which may be exceedingly difficultbased on variations in the distance of the feature from the probe sensorwhen the data is taken. Standardized types and numbers of parameters canbe assigned to various classes of features so as to allow completecharacterization, yet make the matching process more efficient. Forexample, all sessile polyps may be characterized using the maximalwidth, height and base width criteria previously described.

The aforementioned cylindrical coordinate system can also be used as thebasis for image recognition. Specifically, curves “fit” to the digitizedfeatures or nodes may be mathematically rotated around the longitudinalaxis (Z) and iteratively matched to the template(s) in question(according to “point-to-point” methods described subsequently herein).The axis point, i.e., where the longitudinal axis intersects a planedisposed normally within the FOV, is for simplicity assumed to be thegeometric center of the FOV, although more complex techniques forlocating the axis of virtual rotation may be utilized consistent withthe invention. However, through use of ratioed nodal values aspreviously described, such mathematical or virtual rotation may beobviated, since the orientation of the feature in question is notnecessary to compare the feature to the stored templates. Specifically,by determining the characterizing dimensions of the feature, matches forthe ratios formed by the various characterizing dimensions can besearched irrespective of orientation. In a simple analogy, a cubedisposed in the intestinal tract would be recognized to have lengthequal to width equal to height, thereby forming ratios of 1:1 for allmeasurements. Accordingly, the database may then be searched fortemplates having features characterized by one or more 1:1 ratios.Aspect correction (such as that used in the prior art face recognitiontechniques) may also be optionally applied if needed for certain shapesor templates so as to increase the probability of accurate correlation(e.g., to rotate the aforementioned exemplary cube along one or moreaxes).

Alternatively (or in combination), the algorithm of the presentembodiment may be configured to evaluate the feature characteristicsaccording to one or more criterion (deterministic or otherwise) to aidin identification and classification, as compared to the previouslydescribed technique of template comparison. For example, if theheight-to-base width ratio calculated for the feature is less than aprescribed threshold, it may be selectively ignored by the system forfurther processing on the basis that it is likely not a polyp. As yetanother alternative, the software of the system 3500 may be coded togenerate a constellation of close matches to the feature in question forpresentation to the user. Such constellation may be multi-parametric ordimensional. For example, wherein the feature undergoing analysis has aheight-to-maximal width ratio of 2:1, and a height-to-base ratio of 3:1,other features with height-to-maximal width ratios of less than orgreater than 2:1 may form part of the constellation in theheight-to-maximal width dimension, whereas those with height-to-baserations less or more that 3:1 may form part of the constellation in thatlatter dimension. The various dimensions may then be mathematicallycross-correlated to identify those templates which are members of two ormore constellations and have the smallest “distance” from the subjectfeature, with a weighting or other quality factor being assigned basedthereon. Obviously, this type of analysis can be extended to more thantwo constellation dimensions, thereby increasing the accuracy of thetemplate matching process.

In yet another variant of the invention, the system 3500 may beconfigured to generate templates based on data obtained from the sameprobe as under evaluation, such as from visual image data obtained froman earlier (upstream) portion of the intestinal tract. In this fashion,the system database can be updated “on the fly”, and correlationanalysis between features observed in later (downstream) portions of theintestine and those observed further upstream conducted. Such in situtemplate generation may also be used to mask out later features whichare similar or identical. For example, where a first upstream image isanalyzed and determined to be a normal feature (i.e., benign, or notcorrelated to any disease or malady), then one or more templates forthat upstream feature can be generated and used as a basis foreliminating downstream features subsequently detected as also beingbenign or not correlated.

In more sophisticated variants of the present invention, the systemsoftware is adapted to perform digital image matching on apoint-to-point basis, as opposed to the foregoing parametric ratioapproach. Such point-to-point techniques may be more useful where no“standardized” shape or parameter ratios can be defined for a feature ofinterest. A “point-to-point” association in the present context meansthat for any point P in one image, the software can identify which pointQ in the other (e.g., template) image represents the same detail, or ishomologous to P. Hence, digital matching implies that given two digitalviews of an object, the software can find automatically all or asignificant fraction of the pairs of homologous details. For example, inone exemplary variant, the so-called “best correction principle” is usedas the basis for digital matching. Specifically, if r₁(c,l), r₂(c,l) arematrices representing the two digital images undergoing comparison, thentwo homologous details, assimilated to pixels P₁=(c₁, l₁), P₂=(c₂,l₂),should exist identically in both images (i.e., r₁(P₁)=r₂(P₂). However,many non-homologous pairs Q₁,Q₂ may exist such that r₁(Q₁)=r₂(Q₂). But,if two pixels P₁=(c₁,l₁), P₂=(c₂,l₂) are homologous, then their localregions must appear identical, or:vP ₁(c,l)=vP ₂(c,l) for −h≦c≦h, −k≦l≦k,where:vP ₁(c,l)=r ₁(c ₁ +c,l ₁ +l), andvP ₂(c,l)=r ₂(c ₂ +c,l ₂ +l), −h≦c≦h, −k≦l≦k,define two local regions of points P₁,P₂. One measure of the likeness ofthe two local regions comprises the number I(vP1,vP2), defined eitherthrough a distance, for exampleI(vP₁,vP₂)=d₁(vP₁,vP₂)=Σc,l|vP₁(c,l)−vP₂(c,l)|, or alternatively througha correlation index such as I(vP₁,vP₂)=Σc,l vP₁(c,l)vP₂(c,l). Thegreater the similarity of the images, the closer is the value I(vP₁,vP₂)to an optimum obtained with two identical local regions.

As will be appreciated by those of ordinary skill in the software arts,the foregoing equations are coded into the system algorithm in order toperform the required image matching and comparison using the systemdigital processor 3502, or alternatively a dedicated signal processorsuch as the DSPs previously identified herein specifically tasked forsuch computationally intensive algorithms.

The foregoing process is then extended to other points and local regionsof the image as needed in order to establish the requisite level ofconfidence in the match.

Hence, in an exemplary protocol, the image recognition software of theinvention may be configured to screen or scan all or portions of thevisual data stream obtained from a patient in advance of the physician'sreview, and flag or identify frames of potential interest for subsequentreview by the physician. In this fashion, the physician may firstpreview the results of the algorithmic analysis to determine whether anyof the “hits” generated by the algorithm are valid or warrant furtherevaluation, thereby saving time on subsequent evaluation. Furthermore,the algorithmic analysis can be performed while the physician isperforming other tasks in parallel.

While not necessarily a substitute for direct physician observationusing the methods previously described herein, the image recognitionsoftware of the invention is most useful in combination with the othertechniques; i.e., when used in layered fashion. The software mayalternatively be run on only selected portions of data after thephysician has screened them (Or other temporally proximate segments), ineffect acting as a confirmatory check. Or, as yet another alternative,the software may be run contemporaneously with the physician's review;e.g., to flag potential features of interest in one segment of the datastream while the physician reviews other segments in parallel.

It will be recognized that while the foregoing embodiments of theinvention (described with respect to FIGS. 35 and 36 generally) areadapted for processing of the various data streams and signals off-probe(i.e., at the system 3500 or other processing location in datacommunication with the system 3500 and/or probe), the improvements ofthe probe portion of the invention advantageously allow some or even allof the processing to be conducted on-probe, as shown in the exemplarymethod 3700 of FIG. 37. Herein lies an illustration of the inherentbenefit of one particular aspect of the invention, specifically theinclusion of digital data processing on-probe. With software (embeddedor otherwise) disposed and running on-probe, pre-processing of data maybe readily conducted in order to (i) reduce the amount of data requiredto be transmitted off-probe, thereby increasing the speed, efficiency,and robustness of any communications interfaces; (ii) reduce thecomputational loading and/or system requirements of off-probe processingdevices, thereby allowing such devices to be “thinner” (i.e., have lesscapability by virtue of less hardware and/or software); and/or (iii)adjust the data collection and other functions performed by the probe insitu.

For example, portions of the foregoing algorithms described for blankingselected portions of the visual data stream may be incorporated into thesoftware of the probe, such that the probe automatically or autonomously“dumps” data before transmission (or storage in the on-probe storagedevice), thereby reducing the required communications bandwidth for thesystem.

Similarly, the probe can be configured to run algorithms adapted toperform the aforementioned digital image comparison against templatesstored in the probe's memory or another location, and selectivelytransmitting only data or portions of the visual/IR data stream relatingto the features matched by such algorithm, again significantly reducingrequired on-probe data storage and/or communications bandwidthrequirements.

As yet another exemplary alternative, the probe may be configured to runthe foregoing algorithms useful for dividing the data stream into aplurality of segments, and separately transmitting the various segmentsacross two or more separate communication channels, or across the samechannel in actual or permuted order. For example, the data from a givendata stream (or selected portions thereof) can be buffered into theon-probe memory and divided by the algorithm into segments based, forexample on memory address, with the data corresponding to one segment;e.g., from two-byte memory address 00000ACF to 000010CD, beingtransmitted as a block of data distinct from that of the other segments.

It should be recognized that while the foregoing discussion of thevarious aspects of the invention has described specific sequences ofsteps necessary to perform the methods of the present invention, othersequences of steps may be used depending on the particular application.Specifically, additional steps may be added, and other steps deleted asbeing optional. Furthermore, the order of performance of certain stepsmay be permuted, and/or performed in parallel with other steps. Hence,the specific methods disclosed herein are merely exemplary of thebroader methods of the invention.

While the above detailed description has shown, described, and pointedout novel features of the invention as applied to various embodiments,it will be understood that various omissions, substitutions, and changesin the form and details of the device or process illustrated may be madeby those skilled in the art without departing from the invention. Thedescribed embodiments are to be considered in all respects onlyillustrative and not restrictive. The scope of the invention is,therefore, indicated by the appended claims rather than the foregoingdescription. All changes that come within the meaning and range ofequivalence of the claims are to embraced within their scope.

1. A method of processing data derived from a sensor disposed on asubstantially autonomous intestinal probe, said data having beengenerated while said probe moved substantially autonomously through theintestinal tract of a living being, and said processing facilitatingrapid evaluation of said data, comprising: receiving said data at alocation distant from said probe via a network interface; and using acomputerized device having at least one computer program configured torun thereon and in data communication with said network interface,processing at least a portion of said received data at said distantlocation, said processing at said distant location comprising:processing said at least portion of said received data so as to dividesaid at least portion of data into a plurality of frames; generating adisplay comprising a plurality of images, at least a portion of saidplurality of images corresponding to one or more of said frames of saiddivided data; receiving user input as to one or more of said framesbeing selected for review; and presenting pre-stored data for use incomparison to at least one of said selected frames, said comparisonfacilitating identification of one or more physiologic conditions withinsaid subject; wherein said display comprises a computer screen, saidcomputer screen configured to display respective portions of saiddivided data simultaneously in different portions thereof, and saidsimultaneous display decreasing an overall time necessary for reviewingsaid obtained data.
 2. The method of claim 1, wherein said comparison isperformed substantially automatically by a computer program.
 3. Themethod of claim 1, wherein said identification is performedsubstantially automatically by a computer program.
 4. The method ofclaim 1, wherein said processing at least a portion of said receiveddata at said distant location comprises processing said received data ata centralized location that is also configured to receive and processdata associated with at least one other probe.
 5. The method of claim 1,wherein said at least one other probe is disposed at a medical facilitydifferent than that of said substantially autonomous intestinal probe,and is administered by a caregiver other than a caregiver thatadministered said substantially autonomous intestinal probe.
 6. Themethod of claim 1, wherein said (i) division of said at least portion ofdata into a plurality of frames, and said (ii) generating a display,comprises selecting frames of data from a data stream, and forming aseries of snapshots for the user to view.
 7. The method of claim 6,wherein said computer program further comprises a user interfaceconfigured to provide video viewing functions comprising: (i) “fastforward”, (ii) “pause”, and (iii) “reverse”.
 8. The method of claim 1,wherein said display further comprises a user interface having videoviewing functions comprising an image enhancement function.
 9. Themethod of claim 1, wherein said pre-stored data comprises: an image andone or more bytes of textual information providing at least one ofbackground or explanatory information associated with said image. 10.The method of claim 1, further comprises receiving and utilizing dataparticularly and uniquely related to said living being.
 11. The methodof claim 10, wherein said data particularly and uniquely related to saidliving being comprises at least one of: (i) Social Security Number; (ii)name; or (iii) date of administration of said probe within said livingsubject.
 12. The method of claim 10, wherein said data particularly anduniquely related to said living being comprises at least one of: (i)age; (ii) sex, or (iii) ethnicity of said living subject.
 13. The methodof claim 10, wherein said receiving and utilizing data particularly anduniquely related to said living being is performed substantiallycontemporaneously with said act of receiving at least a portion of saidplurality of processed data.
 14. The method of claim 1, wherein said atleast one computer program comprises a program adapted to generate oneor more windows on a display device using a window-based computeroperating system.
 15. The method of claim 1, wherein said pre-storeddata comprises at least one image associated with the intestinal tractof a human being, said intestinal tract having a disease or othermedical abnormality.
 16. A non-transitory computer readable apparatushaving a storage medium and being adapted to store at least one computerprogram thereon, said at least one computer program being configured toprocess at least first and second data derived from at least first andsecond sensors, respectively, said sensors disposed on substantiallyautonomous intestinal probes so as to facilitate rapid viewing thereofby a user, each of said at least first and second sensors being disposedwithin an intestinal tract of a different ones of living beings, thecomputer program which, when executed: receives, at a location distantfrom said probe via a network interface, at least a portion of said atleast first and second data obtained using said at least first andsecond sensors, said at least first and second data generated while saidprobes moved substantially autonomously through the intestinal tract ofsaid living beings; and using a computerized device having at least onecomputer program configured to run thereon and in data communicationwith said network interface, processes at least a portion of saidreceived at least first and second data at said distant location, saidprocessing at said distant location comprising: processing said at leastportion of said received at least first and second data so as tosegregate said at least first and second data into a plurality of framescorresponding to individual ones of said living beings; generation of adisplay having at least two portions, said portions simultaneouslydisplaying data corresponding to said at least first and second sensors,said display comprising a plurality of images, at least a portion ofsaid plurality of images corresponding to one or more of said frames ofsaid divided data; receipt of user input as to one or more of saidframes being selected for review; and presentation of pre-stored datafor use in comparison to at least one of said selected frames, saidcomparison facilitating identification of one or more physiologicconditions within said being.
 17. A method of processing data derivedfrom a sensor disposed on a substantially autonomous intestinal probe,said data having been generated while said probe moved substantiallyautonomously through the intestinal tract of a living being, and saidprocessing facilitating expedient evaluation of said data, said methodcomprising: receiving said data at a different location via a networkinterface; and using a computerized device having at least one computerprogram configured to run thereon and in data communication with saidnetwork interface, processing at least a portion of said received dataat said different location, said processing at said different locationcomprising: processing said at least portion of said received data so asto divide said at least portion of data into at least a first pluralityof frames and second plurality of frames; generating on a displayinformation comprising at least first and second images, said at leastfirst and second images corresponding to respective ones of said atleast first plurality of frames and said second plurality of frames;receiving user input as to one or more of said images being selected forreview; and presenting pre-stored data for use in comparison to at leastone of said selected images, said comparison facilitating identificationof one or more physiologic conditions within said subject; wherein saiddisplay comprises a computer screen, said computer screen configured todisplay said first and second images simultaneously in differentportions thereof, said simultaneous display decreasing an overall timenecessary for reviewing said obtained data.
 18. The method of claim 17,wherein said comparison is performed substantially automatically by acomputer program.
 19. The method of claim 17, wherein saididentification is performed substantially automatically by a computerprogram.
 20. The method of claim 17, wherein said processing at least aportion of said received data at said different location comprisesprocessing said received data at a centralized location that is alsoconfigured to receive and process data associated with at least oneother probe.
 21. The method of claim 20, wherein said at least one otherprobe is disposed at a medical facility different than that of saidsubstantially autonomous intestinal probe, and is administered by acaregiver other than a caregiver that administered said substantiallyautonomous intestinal probe.
 22. The method of claim 17, wherein saiddivision of said at least portion of data into at least said first andsecond pluralities of frames comprises dividing said at least portioninto substantially equal temporal segments.
 23. The method of claim 22,wherein said computer program further comprises a user interfaceconfigured to provide video viewing functions comprising: (i) “fastforward”, (ii) “pause”, and (iii) “reverse”.
 24. The method of claim 17,wherein said display further comprises a user interface having videoviewing functions comprising an image enhancement function.
 25. Themethod of claim 17, wherein said pre-stored data comprises: one or moreimages; and one or more bytes of textual information providing at leastone of background or explanatory information associated with said one ormore images.
 26. The method of claim 17, further comprises receiving andutilizing data particularly and uniquely related to said living being.27. The method of claim 26, wherein said data particularly and uniquelyrelated to said living being comprises at least one of: (i) SocialSecurity Number; (ii) name; or (iii) date of administration of saidprobe within said living subject.
 28. The method of claim 26, whereinsaid data particularly and uniquely related to said living beingcomprises at least one of: (i) age; (ii) sex, or (iii) ethnicity of saidliving subject.
 29. The method of claim 26, wherein said receiving andutilizing data particularly and uniquely related to said living being isperformed substantially contemporaneously with said act of receiving atleast a portion of said plurality of processed data.
 30. The method ofclaim 17, wherein said at least one computer program comprises a programadapted to generate one or more windows on a display device using awindow-based computer operating system.
 31. The method of claim 30,wherein said pre-stored data comprises at least one image associatedwith the intestinal tract of a human being, said intestinal tract havinga disease or other medical abnormality.
 32. A method of processing dataderived from a sensor disposed on a substantially autonomous intestinalprobe, said data having been generated while said probe movedsubstantially autonomously through the intestinal tract of a livingbeing, and said processing facilitating expedient evaluation of saiddata, said method comprising: receiving said data at a differentlocation via a network interface means; and using a computerized meanshaving at least one computer program configured to run thereon and indata communication with said network interface means, processing atleast a portion of said received data at said different location, saidprocessing at said different location comprising: processing said atleast portion of said received data so as to divide said at leastportion of data into at least a first plurality of frames and secondplurality of frames; generating a display comprising at least first andsecond images, said at least first and second images corresponding torespective ones of said at least first plurality of frames and saidsecond plurality of frames; receiving user input as to one or more ofsaid images being selected for review; and presenting pre-stored datafor use in comparison to at least one of said selected images, saidcomparison facilitating identification of one or more physiologicconditions within said subject; wherein said generating a displaycomprises generating said first and second images on a a computerdisplay means, said computer display means configured to display saidfirst and second images simultaneously in different portions thereof,said simultaneous display decreasing an overall time necessary forreviewing said obtained data.
 33. Apparatus for processing data derivedfrom a sensor disposed on a substantially autonomous intestinal probe,said data having been generated while said probe moved substantiallyautonomously through the intestinal tract of a living being, and saidprocessing facilitating expedient evaluation of said data, saidapparatus comprising: a network interface configured to enable receiptof said data at a different location from that of said probe; and acomputerized device having a display device and at least one computerprogram configured to run thereon and in data communication with saidnetwork interface, said computerized device being configured to processat least a portion of said received data by at least: processing said atleast portion of said received data so as to divide said at leastportion of data into at least a first plurality of frames and secondplurality of frames; generating on said display device informationcomprising at least first and second images, said at least first andsecond images corresponding to respective ones of said at least firstplurality of frames and said second plurality of frames; receiving userinput as to one or more of said images being selected for review; andpresenting pre-stored data for use in comparison to at least one of saidselected images, said comparison facilitating identification of one ormore physiologic conditions within said subject; wherein said computerscreen displays said first and second images simultaneously in differentportions thereof, said simultaneous display decreasing an overall timenecessary for reviewing said obtained data.
 34. The apparatus of claim33, wherein said comparison is performed substantially automatically bysaid at least one computer program.
 35. The apparatus of claim 33,wherein said identification is performed substantially automatically bysaid at least one computer program.
 36. The apparatus of claim 33,wherein said apparatus is disposed at a centralized location that isalso configured to receive and process data associated with at least oneother probe.
 37. The apparatus of claim 33, wherein said division ofsaid at least portion of data into at least said first and secondpluralities of frames comprises dividing said at least portion intosubstantially equal temporal segments.
 38. The apparatus of claim 37,wherein said computer program further comprises a user interfaceconfigured to provide video viewing functions comprising: (i) “fastforward”, (ii) “pause”, and (iii) “reverse”.
 39. The apparatus of claim33, wherein said pre-stored data comprises: one or more images; and oneor more bytes of textual information providing at least one ofbackground or explanatory information associated with said one or moreimages.
 40. The apparatus of claim 33, further comprises receiving andutilizing data particularly and uniquely related to said living being,said data comprising at least one of: (i) Social Security Number; or(ii) date of administration of said probe within said living subject.41. The apparatus of claim 40, wherein said receiving and utilizing dataparticularly and uniquely related to said living being is performedsubstantially contemporaneously with said act of receiving at least aportion of said plurality of processed data.
 42. The apparatus of claim33, wherein: said at least one computer program comprises a programadapted to generate one or more windows on a display device using awindow-based computer operating system; and said pre-stored datacomprises at least one image associated with the intestinal tract of ahuman being, said intestinal tract having a disease or other medicalabnormality.